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Sexual Precocity in a 16-Month-Old
4 A% b$ ~; P* VBoy Induced by Indirect Topical
0 y# I; U7 `: F1 d) S0 _0 D# cExposure to Testosterone
$ R. d7 s* h2 N! ]% |Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2. U7 C3 `# s5 B" {- d+ [; J
and Kenneth R. Rettig, MD1  s; n9 F  u' ^
Clinical Pediatrics
, J/ f4 E+ A) T5 f" r4 h! L+ aVolume 46 Number 6
! T, X2 b8 F1 g: XJuly 2007 540-543
, o6 R9 j; @- D4 U% A© 2007 Sage Publications3 l- O& g3 c0 H* n/ B' e
10.1177/0009922806296651
7 `- u/ w2 m' Ahttp://clp.sagepub.com2 ^* i% q' M- h0 e! X
hosted at/ j$ X4 a, P/ S+ I- G
http://online.sagepub.com
: T, h; j% v* |! m+ @Precocious puberty in boys, central or peripheral,% N7 O2 x0 N1 b8 Q
is a significant concern for physicians. Central
5 `' F& ^  e, d8 l5 I% M3 m4 Kprecocious puberty (CPP), which is mediated: d- E( W: L; Q- ]7 |% w9 N7 r
through the hypothalamic pituitary gonadal axis, has/ T5 z( O$ n5 q1 e) p- }/ m
a higher incidence of organic central nervous system# @5 ^6 S  b/ R8 g5 W1 u
lesions in boys.1,2 Virilization in boys, as manifested4 S3 a/ i: D: D
by enlargement of the penis, development of pubic7 i0 P. j" r- j( e
hair, and facial acne without enlargement of testi-
0 y6 _+ s% }, r+ {- U: [cles, suggests peripheral or pseudopuberty.1-3 We& w# C6 \3 x2 J& K0 A1 `
report a 16-month-old boy who presented with the
* f! N( [$ o+ e5 e# Qenlargement of the phallus and pubic hair develop-6 w3 Y* E8 {7 i# b' D; Z
ment without testicular enlargement, which was due; J' }, P3 |6 H8 k% L
to the unintentional exposure to androgen gel used by
0 e2 V( J; a( k3 qthe father. The family initially concealed this infor-/ {5 v, P! u$ d; O
mation, resulting in an extensive work-up for this: `5 K, I& A' Q- F# @' \0 E3 d
child. Given the widespread and easy availability of
6 l3 a9 O% z3 c5 N9 ctestosterone gel and cream, we believe this is proba-
( c3 y7 m, y, Q8 l) e! @  T5 ]( wbly more common than the rare case report in the
4 j6 r. s, o3 ], Q; F0 R3 i/ Bliterature.41 ~+ Z. F6 k0 m$ y
Patient Report
+ \; A% _8 C) U. R; UA 16-month-old white child was referred to the
8 }) s* ?! I; zendocrine clinic by his pediatrician with the concern
. d) \/ f- D/ Uof early sexual development. His mother noticed' \# I: \! u% y4 p1 s" s7 e* ]* u
light colored pubic hair development when he was
3 w+ c' [' o* Q( |& S5 qFrom the 1Division of Pediatric Endocrinology, 2University of
& a; S5 l( i# l- u  p* LSouth Alabama Medical Center, Mobile, Alabama.5 m. ~% F4 E9 ~$ Y' i/ o
Address correspondence to: Samar K. Bhowmick, MD, FACE,
: P: S9 h4 E# c2 e5 m: C' [' e% kProfessor of Pediatrics, University of South Alabama, College of
. {& c" p+ q; G! |: ^  jMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
9 N/ H$ Q, _7 J8 b. Ae-mail: [email protected].3 D5 @% t3 W8 a: B0 \1 ]1 o5 R
about 6 to 7 months old, which progressively became* M( g# c# `* C5 {! [7 F( }
darker. She was also concerned about the enlarge-
# g( y( ?- |) e8 a% n" ement of his penis and frequent erections. The child5 x/ ^/ R/ V: r: u) c$ g
was the product of a full-term normal delivery, with" U# n* C: w5 m# H6 Q# e
a birth weight of 7 lb 14 oz, and birth length of. S1 A* ^# e* S
20 inches. He was breast-fed throughout the first year( X) ^& Y# F% C. R' W- k
of life and was still receiving breast milk along with5 Y# N8 X( Y: p: s, J
solid food. He had no hospitalizations or surgery,0 H7 E9 e6 T7 l
and his psychosocial and psychomotor development
& U9 W1 a0 g1 p* T! {; I7 j( rwas age appropriate.' X! D+ G/ i8 H6 ?0 p7 E) i0 v
The family history was remarkable for the father,: r3 U# ~* T, K; X) T0 K
who was diagnosed with hypothyroidism at age 16,
* j! `( ]2 K' M5 M- n/ _; z9 [which was treated with thyroxine. The father’s' b- h6 Y6 I5 i" T1 J
height was 6 feet, and he went through a somewhat) d, ^. W& r& s
early puberty and had stopped growing by age 14.
7 q* W: h0 K& L2 p8 e6 x/ I+ ^The father denied taking any other medication. The
- }4 u6 q6 Z4 J9 i# n2 c, Bchild’s mother was in good health. Her menarche* J' y4 [2 F, s! J0 h- F7 `
was at 11 years of age, and her height was at 5 feet$ c: C$ w- W, S9 D
5 inches. There was no other family history of pre-
/ d. O' o: P& Ncocious sexual development in the first-degree rela-
2 r1 h$ z$ |2 H5 ~6 Q$ jtives. There were no siblings.2 Z* U! }' D1 c' |# _
Physical Examination* F' H/ V" R- O& K8 W
The physical examination revealed a very active,
' D2 e. v+ e& P/ Q: \playful, and healthy boy. The vital signs documented' Y1 {6 E0 O8 c* f; Q+ X
a blood pressure of 85/50 mm Hg, his length was
3 o, M; R  D. Q3 z: D90 cm (>97th percentile), and his weight was 14.4 kg
0 A' c1 x6 v8 ](also >97th percentile). The observed yearly growth
5 v3 m$ a  H1 [- [, qvelocity was 30 cm (12 inches). The examination of$ S4 l! Y8 W) i$ C, z/ E! g
the neck revealed no thyroid enlargement.% e/ c' `2 v6 y( A1 D: k
The genitourinary examination was remarkable for, n# j) |0 i/ d' Z( }( i  M2 L3 Q8 r3 b
enlargement of the penis, with a stretched length of) R5 o2 ]( G3 y9 y
8 cm and a width of 2 cm. The glans penis was very well; v7 h3 k5 }9 _$ o+ l. U) q
developed. The pubic hair was Tanner II, mostly around
$ T4 W* A& ~  p5401 H3 v2 F; m5 p- U9 C
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from  D% {# ~( v5 v1 [! f0 P8 F; r
the base of the phallus and was dark and curled. The
5 l2 G9 v' P! `- Rtesticular volume was prepubertal at 2 mL each.
/ D2 u8 O. f+ v( ]3 F/ Y: RThe skin was moist and smooth and somewhat; }# K/ ^6 Y, M6 l) j, B! s$ u5 B
oily. No axillary hair was noted. There were no& n- W' m7 L) C$ e7 e- k. Q
abnormal skin pigmentations or café-au-lait spots.
8 J4 }! e3 ~/ }3 k' x+ l& ANeurologic evaluation showed deep tendon reflex 2+
5 e9 \8 R" t0 f9 f% ]& f7 M' ?" gbilateral and symmetrical. There was no suggestion
3 ]' E/ r2 {# Q; Bof papilledema.& P! [+ ~. I6 j" |! I0 J
Laboratory Evaluation
& Q( C# n; N, wThe bone age was consistent with 28 months by* X" g2 q7 m$ m0 x: e5 p/ w
using the standard of Greulich and Pyle at a chrono-: Q$ R0 y) H- q$ B, T0 ?
logic age of 16 months (advanced).5 Chromosomal
7 w8 O& b* C1 ~; U% B/ q* Lkaryotype was 46XY. The thyroid function test9 |: U* _6 M' r
showed a free T4 of 1.69 ng/dL, and thyroid stimu-8 u, G; k0 }; \6 C8 y; I* c
lating hormone level was 1.3 µIU/mL (both normal).
) q0 J4 K- H# B/ _9 U. KThe concentrations of serum electrolytes, blood
. r7 j3 G! o2 c+ ^5 Yurea nitrogen, creatinine, and calcium all were7 A4 S" V/ Q( n1 y) G
within normal range for his age. The concentration, D' |" F+ J$ S
of serum 17-hydroxyprogesterone was 16 ng/dL
$ B) e; V/ m& Q4 d. J6 B(normal, 3 to 90 ng/dL), androstenedione was 20
  H9 J6 P& m1 A" a! vng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
4 n0 ?6 G, [' h! i7 P3 mterone was 38 ng/dL (normal, 50 to 760 ng/dL),. o* h9 P2 J  B% u* T# Y; A8 R9 T  |
desoxycorticosterone was 4.3 ng/dL (normal, 7 to# |1 |5 ]' T4 f* I2 d9 d0 B7 F6 w
49ng/dL), 11-desoxycortisol (specific compound S)
6 _' d' Z' C. K9 x5 O9 x; K6 d8 Qwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
# Y6 `  ]2 m9 ~; |tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ k. P- G" |" g! k" ^5 o
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
0 j* V$ }! b9 [7 y- |5 rand β-human chorionic gonadotropin was less than1 ?: r3 [0 ]/ J8 S& [2 t
5 mIU/mL (normal <5 mIU/mL). Serum follicular
# H, u1 D4 b6 t) v# H  xstimulating hormone and leuteinizing hormone
2 i& s9 D4 P0 E) Q* mconcentrations were less than 0.05 mIU/mL3 U8 F* e) N- k8 o* ]' |) a( O
(prepubertal).! Q# J  R- R" Z$ e1 h/ @
The parents were notified about the laboratory5 v4 c: L0 n6 C( z; z- \8 e4 c) f
results and were informed that all of the tests were' M, ^" p. v5 |2 I5 J0 @
normal except the testosterone level was high. The
% A6 Y3 V& k+ l2 p8 Ifollow-up visit was arranged within a few weeks to
7 r/ t6 G9 Y2 z, n/ Cobtain testicular and abdominal sonograms; how-
* o9 b- t9 J2 O6 _+ {ever, the family did not return for 4 months.
6 N  o- u' E) i: v  ]0 x$ [) Q, CPhysical examination at this time revealed that the
( e8 F7 n& I9 N/ X* Vchild had grown 2.5 cm in 4 months and had gained
( o8 u9 n) ^* F/ O# G' l$ c" m: x2 kg of weight. Physical examination remained
4 K+ F3 l, z( Z, X* }$ P# e+ b! R( Aunchanged. Surprisingly, the pubic hair almost com-* o" F! \" ?5 d$ V
pletely disappeared except for a few vellous hairs at
$ T* q( {: n, N, |the base of the phallus. Testicular volume was still 2
3 {% I7 b7 K" n5 F6 v  LmL, and the size of the penis remained unchanged.
0 R; S" T$ n! M6 P+ p% K0 f6 |: z  t6 ]% VThe mother also said that the boy was no longer hav-
: |% a* F  F: I6 Ping frequent erections.4 m/ i6 J( i) w+ D  D& o( q5 ^' X
Both parents were again questioned about use of
2 H; q  f9 V4 a7 j8 Xany ointment/creams that they may have applied to2 ]* J  ~6 j/ p: F9 G2 I
the child’s skin. This time the father admitted the$ |  v) [8 l& L
Topical Testosterone Exposure / Bhowmick et al 541
5 c: m. z% J# x' l6 a% _! buse of testosterone gel twice daily that he was apply-. G+ E) K) B) `$ E& J
ing over his own shoulders, chest, and back area for
" T7 D4 U% G$ X% w8 ra year. The father also revealed he was embarrassed
" N3 Y, x- z; Q& n1 Bto disclose that he was using a testosterone gel pre-
5 j* F1 O( z5 }/ M$ m- n& ascribed by his family physician for decreased libido" k% t) z; |% \' W$ s' b0 I* Q5 P
secondary to depression.! T# R& @- ?3 H1 H0 n1 X6 }
The child slept in the same bed with parents.
0 e  P6 d! D6 O/ D2 zThe father would hug the baby and hold him on his. X8 h& O1 }3 H; P
chest for a considerable period of time, causing sig-) `( q5 I- k2 L  G
nificant bare skin contact between baby and father.4 y8 j- p7 q& T" n/ u0 ~
The father also admitted that after the phone call,
; C4 q8 Y2 I* o- ^3 |% H' E" Nwhen he learned the testosterone level in the baby
; a0 Y/ ~% h/ B3 Iwas high, he then read the product information
& h* x: E0 C) O# ^packet and concluded that it was most likely the rea-
. [& u( z1 C4 Json for the child’s virilization. At that time, they7 w  `/ q8 R0 {* `- C( {
decided to put the baby in a separate bed, and the$ _1 g! p, b" n8 `
father was not hugging him with bare skin and had
/ R& A2 g( T$ ~7 _3 Ybeen using protective clothing. A repeat testosterone
' f" K6 G: V  C. t) dtest was ordered, but the family did not go to the" f9 \6 g+ T% T* c
laboratory to obtain the test.1 t! z: r! ^% E3 J% m
Discussion! R: k6 _0 n8 x  I" w  _- k
Precocious puberty in boys is defined as secondary( C9 P+ O* l1 _5 p
sexual development before 9 years of age.1,4
! P4 O. L# {  v- Q  F% ]1 F4 Z- yPrecocious puberty is termed as central (true) when, d/ a9 R9 Q9 J6 ~3 u
it is caused by the premature activation of hypo-2 x6 v4 k. D/ m! `4 Q6 L
thalamic pituitary gonadal axis. CPP is more com-
' t5 n7 ~- \! u' J/ z  a% W( ?mon in girls than in boys.1,3 Most boys with CPP/ t& l3 }/ W- E
may have a central nervous system lesion that is
  D) L' M* P. J+ O5 xresponsible for the early activation of the hypothal-
3 }- k! K- K! `- Eamic pituitary gonadal axis.1-3 Thus, greater empha-: Y/ h% d; S8 Z8 y! u
sis has been given to neuroradiologic imaging in1 H7 p) |2 h1 e" N$ X# I6 A
boys with precocious puberty. In addition to viril-
8 I2 Q& e7 c+ L& q: jization, the clinical hallmark of CPP is the symmet-
- m9 r' u" `% }: arical testicular growth secondary to stimulation by; d" w3 j; r7 g4 Z0 O, z& N& ]( o
gonadotropins.1,3
# K' {5 l3 u1 Y8 X- jGonadotropin-independent peripheral preco-
$ ^; h0 E6 ?) f; L* x. D4 W& x- Zcious puberty in boys also results from inappropriate
. O, Z: m8 |9 K1 Bandrogenic stimulation from either endogenous or9 g1 _1 J' l- R( T/ J3 p
exogenous sources, nonpituitary gonadotropin stim-
# l7 |% Y$ O* j* _" P1 p, M! Culation, and rare activating mutations.3 Virilizing
6 Q% `" N5 j' i9 xcongenital adrenal hyperplasia producing excessive
3 g8 W6 G9 a. M5 X* z( vadrenal androgens is a common cause of precocious
! T( [) ^9 E! qpuberty in boys.3,4) L' O8 z  E7 r( N
The most common form of congenital adrenal
* \& j( W/ J" N( ]! S9 ehyperplasia is the 21-hydroxylase enzyme deficiency.+ N* K5 Z/ L4 N9 J
The 11-β hydroxylase deficiency may also result in
1 _1 T2 F4 @. s* eexcessive adrenal androgen production, and rarely,, W9 M' e  R, Y
an adrenal tumor may also cause adrenal androgen2 m" b6 g/ D; S* Z0 e
excess.1,3
! |6 p  g+ A; T1 h* k6 N0 \' K3 ^at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from: n" A3 \4 e# M- c- u
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
1 V+ J, q, L4 X  AA unique entity of male-limited gonadotropin-
  ?9 J- g9 ]! lindependent precocious puberty, which is also known
9 y2 ~1 c2 d. Z9 l: w7 Fas testotoxicosis, may cause precocious puberty at a
' C8 C* v  H5 I* B2 w0 ?1 X, i( t  Vvery young age. The physical findings in these boys
& m% Z) l: t& _5 F$ ewith this disorder are full pubertal development,
$ G* H' v: Y9 I. h9 dincluding bilateral testicular growth, similar to boys
( v' T( h6 Y6 Z/ }9 e- Y. X: cwith CPP. The gonadotropin levels in this disorder6 a$ }2 a: R( s4 K) v
are suppressed to prepubertal levels and do not show. ]0 g$ B& {( t) ]7 c+ z3 V
pubertal response of gonadotropin after gonadotropin-
$ q4 C) I4 P6 h! D6 ureleasing hormone stimulation. This is a sex-linked! Q) |2 n2 `- `% k
autosomal dominant disorder that affects only
  o8 b8 U. {/ |! p& e4 u! Kmales; therefore, other male members of the family
( X1 ]. s+ z) c7 X& A# j7 U% Vmay have similar precocious puberty.36 }) [/ L" ]) Q& r0 q6 H
In our patient, physical examination was incon-
) i4 @" [1 y7 I. _, c( osistent with true precocious puberty since his testi-
( n. X0 {" |. }- |cles were prepubertal in size. However, testotoxicosis7 M4 D4 s* w+ Q1 R/ s
was in the differential diagnosis because his father
1 m5 u, I- m3 [* p) U% Lstarted puberty somewhat early, and occasionally,$ d7 [  g8 k* n: ?7 d
testicular enlargement is not that evident in the* Z: Z3 _" y2 N. `# _2 J, Z, l
beginning of this process.1 In the absence of a neg-* B8 L1 v7 {3 V2 Y" ]3 h
ative initial history of androgen exposure, our
  N  D* t* U  {% H" K# Qbiggest concern was virilizing adrenal hyperplasia,) Q- u' ~" @3 w, E- C" `# g" z$ @
either 21-hydroxylase deficiency or 11-β hydroxylase6 `! |% p" B/ @/ i- `
deficiency. Those diagnoses were excluded by find-
6 W( V" A9 f3 \: n  ving the normal level of adrenal steroids.; j  M( P2 O+ Z/ v. K+ Z. S0 z, }
The diagnosis of exogenous androgens was strongly
/ [. c8 y* R# k' ?6 E4 C6 N3 Ssuspected in a follow-up visit after 4 months because
  F. {1 y  X$ B7 s# K$ ?the physical examination revealed the complete disap-
  Z! M1 ?! B" n6 |8 Y( m# P$ V+ qpearance of pubic hair, normal growth velocity, and& \2 z$ @" Y8 i# Q! A% y; A1 C
decreased erections. The father admitted using a testos-) R: W  |( z+ _
terone gel, which he concealed at first visit. He was" R3 _5 @! n$ d* T4 }
using it rather frequently, twice a day. The Physicians’. w* d) D! W4 I) K
Desk Reference, or package insert of this product, gel or
6 f+ a" L# T0 q3 Acream, cautions about dermal testosterone transfer to; v! P; S5 c6 N& _& u4 F
unprotected females through direct skin exposure.3 f. \6 F& Z8 u# e+ x! F
Serum testosterone level was found to be 2 times the: }' O0 U0 Z/ I& X$ M3 m5 t
baseline value in those females who were exposed to- _# q0 l7 h# {1 D/ x
even 15 minutes of direct skin contact with their male  h" q0 j, T' ~* n- E) T+ u
partners.6 However, when a shirt covered the applica-
' s" g& w* _) V0 M# k" ution site, this testosterone transfer was prevented.
7 |; v/ y/ C% t+ Y2 OOur patient’s testosterone level was 60 ng/mL,
9 G/ ^' [; M$ ewhich was clearly high. Some studies suggest that
5 y0 S# r4 o* Hdermal conversion of testosterone to dihydrotestos-2 D6 Q6 ~1 [3 \4 O
terone, which is a more potent metabolite, is more6 z! t* _% B6 X3 b  V) T6 B
active in young children exposed to testosterone
0 ~1 ]' Y( [- \9 H- ~' H6 o5 V) iexogenously7; however, we did not measure a dihy-
0 |; q" z6 W1 M+ }drotestosterone level in our patient. In addition to
9 Y( m3 L7 L2 q. ~7 a# k4 x8 svirilization, exposure to exogenous testosterone in
: \- v& T9 O" q, gchildren results in an increase in growth velocity and
( s0 H$ e; m8 {5 ]0 K. \advanced bone age, as seen in our patient." q& e7 J9 a- D2 e3 _! l
The long-term effect of androgen exposure during
' c5 l" K8 A5 m$ ~7 A% D! @early childhood on pubertal development and final
2 [! k7 ^- \/ S( y$ Cadult height are not fully known and always remain- }1 C! f& c0 l2 V: v
a concern. Children treated with short-term testos-/ Q8 z( C0 s3 E1 n
terone injection or topical androgen may exhibit some% z6 B  [2 n$ y4 q9 t
acceleration of the skeletal maturation; however, after$ f, N  A. C. p# {, B
cessation of treatment, the rate of bone maturation
" }: N# H! D, A1 b5 Vdecelerates and gradually returns to normal.8,97 {' S  x# w. _" H$ m
There are conflicting reports and controversy- m: V7 ]( y4 I+ z  G# ?
over the effect of early androgen exposure on adult3 a" I/ b7 ~+ ]1 V) S5 ]
penile length.10,11 Some reports suggest subnormal
" F7 E" Q" R9 d# z# D% Vadult penile length, apparently because of downreg-
: V6 z$ j4 X9 y2 Bulation of androgen receptor number.10,12 However,- r. k9 |( c& I8 ]6 j- [- g. k; t
Sutherland et al13 did not find a correlation between# q2 Z" ^2 O9 z: k) X! t
childhood testosterone exposure and reduced adult
8 R# \/ F( b5 n2 \- e2 bpenile length in clinical studies.( z  K- r% u' b8 T- f# }) R
Nonetheless, we do not believe our patient is, L' U, C7 x3 b% l
going to experience any of the untoward effects from% w& I  f# K7 [. w: M5 J, r
testosterone exposure as mentioned earlier because
( }7 q: u+ o5 i* @* T% othe exposure was not for a prolonged period of time.3 A  @; G' V7 Y' ^  V. l! `2 |+ X
Although the bone age was advanced at the time of
5 w5 Q( H  K; A! J) s/ ]diagnosis, the child had a normal growth velocity at+ W9 q: s8 q: F2 m/ o& a
the follow-up visit. It is hoped that his final adult% X/ P. I& J+ X: l& G9 L
height will not be affected.
7 V  Y) x& N+ g4 o, s) B$ i  Z6 RAlthough rarely reported, the widespread avail-
( K9 P# [8 s& h8 K  Dability of androgen products in our society may
; z* Z/ Y  |( w" H, eindeed cause more virilization in male or female! x8 w* m7 u% d. I
children than one would realize. Exposure to andro-
7 h9 M6 `2 D% \. O! j/ E' f& P# Ygen products must be considered and specific ques-, U% d8 B; o$ c- }$ e1 t5 U
tioning about the use of a testosterone product or
( g$ R0 Y- U) z9 @0 @$ ~5 s1 cgel should be asked of the family members during
. r! j7 g9 D  ^( ^the evaluation of any children who present with vir-
1 O- u7 r2 z( X0 U% Zilization or peripheral precocious puberty. The diag-
8 Q% z3 S( j( X& }nosis can be established by just a few tests and by4 ~5 F9 C! W' @2 D* R: L* D
appropriate history. The inability to obtain such a
7 _. D/ P3 u4 a. \' G  Ghistory, or failure to ask the specific questions, may
. U& Z7 i8 {% N, S& zresult in extensive, unnecessary, and expensive
2 H' {* \# k5 I- [investigation. The primary care physician should be
4 `& z  C8 h3 }* u; b! taware of this fact, because most of these children2 r2 \5 ^6 R) L2 U) u
may initially present in their practice. The Physicians’
; X7 k# r( x. e7 h9 `Desk Reference and package insert should also put a) M# ^: n( v2 {' l( Q: N4 y0 |9 A1 f
warning about the virilizing effect on a male or
' d2 o! |( D8 ?6 nfemale child who might come in contact with some-& h: q5 i1 l6 c, Y
one using any of these products.
6 P- S9 w8 u# L5 zReferences
( A: @  h- l5 {1. Styne DM. The testes: disorder of sexual differentiation
$ z& _* m; k/ t' @/ @  H: xand puberty in the male. In: Sperling MA, ed. Pediatric
' @, {2 O9 L! ~4 a3 x6 V% TEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
1 r5 H5 a8 e( E# Z- ]2002: 565-628." Q1 i: E. i. b% X3 H
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
8 o& i6 Z$ |7 ~puberty 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
5 n( \* g  l' |7 ?5 k7 f" J' GBoy Induced by Indirect Topical4 q3 l& @. K4 T% c2 _/ y8 y1 ~
Exposure to Testosterone
  L2 h9 P6 g5 K9 ^4 J0 cSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
% f% m2 W! {! Z# l: z% z  P& y! P% Mand Kenneth R. Rettig, MD1
4 e. M, a) t# y& nClinical Pediatrics5 P3 c; R) g& o" D" f
Volume 46 Number 6" g, u/ p( Y2 n% \6 M. M" _
July 2007 540-543: W* [1 T2 l6 P9 X0 @
© 2007 Sage Publications
" p% |( U& \  `- e; B10.1177/0009922806296651
3 s6 c% i6 N; k' e+ B, L  h- Fhttp://clp.sagepub.com9 n2 n' g& g/ w. }& }+ P
hosted at) P8 Z7 N+ s0 ~% O; i( t
http://online.sagepub.com) S9 I) H5 F, |, ^
Precocious puberty in boys, central or peripheral,
7 n7 Y" r6 }/ K& tis a significant concern for physicians. Central
2 X  r+ R& w2 C' C- [9 pprecocious puberty (CPP), which is mediated
/ {/ R, {6 o  I# Bthrough the hypothalamic pituitary gonadal axis, has
# ^; A; t0 O- t  n; O, d( Ea higher incidence of organic central nervous system
# @/ \6 c: _7 }/ N+ Ilesions in boys.1,2 Virilization in boys, as manifested& P: K$ \# R1 P$ s
by enlargement of the penis, development of pubic, K& R7 W( s" l$ L
hair, and facial acne without enlargement of testi-6 O8 q" l5 D* h- `5 O
cles, suggests peripheral or pseudopuberty.1-3 We, |% V; u4 T- H# ]+ i. q
report a 16-month-old boy who presented with the
+ i  h( b+ L7 ^1 ^; d0 {$ Jenlargement of the phallus and pubic hair develop-  b. |' Z- Z, G2 J- B
ment without testicular enlargement, which was due/ ?7 n, G- G7 o7 R, C2 c+ \
to the unintentional exposure to androgen gel used by
" [2 }( I$ _. S3 h. Q* N6 ethe father. The family initially concealed this infor-
, R/ R' {9 [% A' J! W0 vmation, resulting in an extensive work-up for this
3 s2 g: }% Q& X: J; k  \child. Given the widespread and easy availability of
3 ]3 f7 ~6 S  u6 `testosterone gel and cream, we believe this is proba-4 R. e# L4 X# T* R" ?
bly more common than the rare case report in the
* Z$ Q. k+ d0 T# f( Eliterature.4) }+ \+ \8 ?5 y4 t' q% `
Patient Report
' C+ Y% U& T3 [4 ?, jA 16-month-old white child was referred to the9 e/ ?9 E; o5 p/ h  I& H. v. j
endocrine clinic by his pediatrician with the concern
) @' i5 v# p9 eof early sexual development. His mother noticed0 a, l8 }0 b! ^' f9 ^
light colored pubic hair development when he was
  @6 X8 C' R% v! _+ n& UFrom the 1Division of Pediatric Endocrinology, 2University of# j: s0 Y7 }) k; z5 |
South Alabama Medical Center, Mobile, Alabama.
' s. L5 R' o+ ?9 k" JAddress correspondence to: Samar K. Bhowmick, MD, FACE,
5 X* N& ~2 U8 XProfessor of Pediatrics, University of South Alabama, College of* M: o3 M7 B  X
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! i; m& Q  f/ e; {  ~9 o7 N7 I) ze-mail: [email protected].4 P1 i: k7 J# F. {" L. K
about 6 to 7 months old, which progressively became8 O' M5 C+ s5 `
darker. She was also concerned about the enlarge-0 Z! j4 S7 v$ e# \1 _. W
ment of his penis and frequent erections. The child; e7 O. {* F6 ]
was the product of a full-term normal delivery, with+ C% B( c  L) p" A4 L7 e  g% A
a birth weight of 7 lb 14 oz, and birth length of
4 [7 _9 s; u$ _' J. t20 inches. He was breast-fed throughout the first year
" |% n0 R1 _7 oof life and was still receiving breast milk along with
( W' H3 g$ b* I+ Ysolid food. He had no hospitalizations or surgery,
* l' M5 j* _9 tand his psychosocial and psychomotor development& |0 U  @9 x, B5 q
was age appropriate.& ]5 s% x' W) J" {% r# ^
The family history was remarkable for the father,
3 I0 n- ]7 P/ ]0 _who was diagnosed with hypothyroidism at age 16,
6 A/ o$ `) c. s+ n# G* Vwhich was treated with thyroxine. The father’s3 W9 g+ w5 x6 R/ {# m6 U
height was 6 feet, and he went through a somewhat
/ E7 s0 d0 ^2 O7 ?, }( \* y1 Q8 V6 vearly puberty and had stopped growing by age 14.! d( H. r' {: _
The father denied taking any other medication. The8 ^# M9 D. l4 _, o. |* w. l
child’s mother was in good health. Her menarche
# Y; W/ q- V5 Z5 Y( o) _: xwas at 11 years of age, and her height was at 5 feet
7 ?; ?" J$ O4 g5 inches. There was no other family history of pre-
0 N5 ^) x: r( dcocious sexual development in the first-degree rela-
- b: L3 p# W: f: \; xtives. There were no siblings.2 S  M% I# i2 E, O- S
Physical Examination1 {& i( N% T8 ^8 g2 x
The physical examination revealed a very active,
/ K" N  x. V6 T. t7 {) g5 Q; b! t2 jplayful, and healthy boy. The vital signs documented. f( ]" K* ^; L* X2 F: N
a blood pressure of 85/50 mm Hg, his length was; G' H$ b, n( O' ^& V2 x
90 cm (>97th percentile), and his weight was 14.4 kg/ e3 v/ q7 j% K# R/ n: H4 }
(also >97th percentile). The observed yearly growth
6 u8 f# w5 h$ R  l) r8 Lvelocity was 30 cm (12 inches). The examination of! {! d7 C% O3 F' G. z' H  g  u
the neck revealed no thyroid enlargement.& {2 S$ ^8 t: N: e' W! {
The genitourinary examination was remarkable for* z/ Y5 w" P3 E. o  \
enlargement of the penis, with a stretched length of/ x, m& ?; t1 ~' K9 g2 u
8 cm and a width of 2 cm. The glans penis was very well
  R* B' O) G3 i" Adeveloped. The pubic hair was Tanner II, mostly around
5 Z' z8 ]( E9 H" q1 i% _; e4 X540
) h5 m- H% f6 ]$ _5 ~5 d$ {, nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
1 X/ A  M( l$ N& `& I$ Z* Rthe base of the phallus and was dark and curled. The
$ u% C* [& f1 f- e2 k. _* ]testicular volume was prepubertal at 2 mL each.8 L2 H3 C& _" G8 ^
The skin was moist and smooth and somewhat0 J( T3 D2 r5 z7 g! Z# {$ ?
oily. No axillary hair was noted. There were no
9 \) U: j/ I7 U, I% u/ f6 aabnormal skin pigmentations or café-au-lait spots.
( Y; a. q: T3 S4 ]/ NNeurologic evaluation showed deep tendon reflex 2+6 ~3 J6 Q' j: N, Z$ W7 ^# D7 c
bilateral and symmetrical. There was no suggestion$ B' z; w2 I" Y2 g6 x& U" q, k# {
of papilledema./ J7 G  k7 C% a2 A4 |& B' j
Laboratory Evaluation
; a& M7 {. g# C/ d  ~1 z% _) pThe bone age was consistent with 28 months by" f9 h* `, n6 r9 B8 S
using the standard of Greulich and Pyle at a chrono-: {* m8 j9 w; K9 v3 Y- w
logic age of 16 months (advanced).5 Chromosomal- q. ~7 j9 d1 C/ O
karyotype was 46XY. The thyroid function test
1 n, Y3 e7 c& e3 |: j7 z9 k# u5 Fshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
9 ~# n9 X+ b! v! q# C4 Rlating hormone level was 1.3 µIU/mL (both normal).
; t9 ~2 y' k) T7 {4 bThe concentrations of serum electrolytes, blood
, i% ?3 {" G4 C5 Turea nitrogen, creatinine, and calcium all were% K( T% J- ~% ~( E" L4 t
within normal range for his age. The concentration  }) _9 x5 H8 k1 L* H2 k
of serum 17-hydroxyprogesterone was 16 ng/dL
4 q& d  P0 j7 P(normal, 3 to 90 ng/dL), androstenedione was 20
& A# K1 ]# Z8 ?; _4 G; ]ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
- C+ p5 g0 x9 W8 K! Hterone was 38 ng/dL (normal, 50 to 760 ng/dL),6 Y$ Y' I9 `3 X9 p8 q' C
desoxycorticosterone was 4.3 ng/dL (normal, 7 to5 F* w8 O% ?& ?  Q0 \. s
49ng/dL), 11-desoxycortisol (specific compound S)0 N5 ?5 A- t8 \# J" r
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 n3 D! g; t: r; }tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total1 v1 P9 H6 B) A
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),9 `/ p2 |3 d; J/ d; |
and β-human chorionic gonadotropin was less than8 r$ ?5 ]( w+ ]2 c. b- }$ b
5 mIU/mL (normal <5 mIU/mL). Serum follicular
8 ^$ Z* {" G. o( @/ V. kstimulating hormone and leuteinizing hormone0 S7 ^, O7 P' E! F( z" k) \
concentrations were less than 0.05 mIU/mL
/ P3 {" N& Q9 X4 c) |/ Z(prepubertal).
; ~; R3 E7 y% G+ x1 X! `) o: E/ ]The parents were notified about the laboratory. j  `0 B, V  K0 D
results and were informed that all of the tests were
7 B* x2 a1 ]2 d$ unormal except the testosterone level was high. The
( H2 s" o. h! R' M6 }follow-up visit was arranged within a few weeks to
( E7 M2 [$ `$ @, k# U  Robtain testicular and abdominal sonograms; how-
1 P6 l: ~0 E2 @8 dever, the family did not return for 4 months.
$ ?. P" Y& n9 i# f) RPhysical examination at this time revealed that the# e! g% T5 q, A% P0 u7 j5 [* N7 V
child had grown 2.5 cm in 4 months and had gained
7 e  p7 k2 q& s0 d& T. E, X2 kg of weight. Physical examination remained% u2 _5 H$ k0 {
unchanged. Surprisingly, the pubic hair almost com-' K, ]1 g% S# e& D( ?4 B
pletely disappeared except for a few vellous hairs at
  I1 e' J9 F) j% _9 N  xthe base of the phallus. Testicular volume was still 2
' o+ N( A3 v' V; X( LmL, and the size of the penis remained unchanged.
% R# z: E% m6 _- F7 eThe mother also said that the boy was no longer hav-' o$ U; f4 F8 s: a
ing frequent erections.
9 }  f# i5 z7 _( V  JBoth parents were again questioned about use of
  s" z: k5 H1 Q" L6 y9 vany ointment/creams that they may have applied to1 c% E; T. |# e2 W
the child’s skin. This time the father admitted the  `; }6 p3 K8 `" n
Topical Testosterone Exposure / Bhowmick et al 5411 c/ J# m+ e/ ^" O! T3 f  C
use of testosterone gel twice daily that he was apply-" F5 t: s& w6 d
ing over his own shoulders, chest, and back area for. q5 k; N/ v0 g: O
a year. The father also revealed he was embarrassed
* a8 V- N5 Q1 K. @- Gto disclose that he was using a testosterone gel pre-& Y8 N, u2 k) K8 O+ O+ p
scribed by his family physician for decreased libido7 B5 ?4 D- o2 W% w' ]& b
secondary to depression.4 o8 {9 ~$ D  w/ \8 d
The child slept in the same bed with parents.
9 Z( k3 M8 I, QThe father would hug the baby and hold him on his9 J) d) g% H& `" Q
chest for a considerable period of time, causing sig-
0 @+ U" t) V% [! s7 r  ^6 k; pnificant bare skin contact between baby and father.
. D# F- ^, m: Z1 iThe father also admitted that after the phone call,: [' }% b2 U/ \+ V, @
when he learned the testosterone level in the baby; q5 ^; e8 Z" R4 L+ v- N& x
was high, he then read the product information
* l$ n$ H- M! O: q- v4 xpacket and concluded that it was most likely the rea-% K' W- J( I  l2 x/ C) L
son for the child’s virilization. At that time, they5 d  }# k  G+ M
decided to put the baby in a separate bed, and the
; K9 E* u! s4 D. \/ u. J7 `0 [! rfather was not hugging him with bare skin and had6 g2 X, h2 n; r& d) s. M& x
been using protective clothing. A repeat testosterone9 n$ I) C- A( y
test was ordered, but the family did not go to the
, p& ^- L, k$ S5 l, C4 Glaboratory to obtain the test.$ d* F/ N- m  A- f" ]. @" P5 J
Discussion" q* T4 r0 p8 R! z5 Z! X4 M
Precocious puberty in boys is defined as secondary
! c6 \" I. s1 n6 N- _, Zsexual development before 9 years of age.1,4  _( _  u  q8 H0 `! ?, e
Precocious puberty is termed as central (true) when
7 T6 {$ l) a' _1 d; c; hit is caused by the premature activation of hypo-5 t, @4 J$ X9 L7 W& C: _
thalamic pituitary gonadal axis. CPP is more com-
$ x4 ^! c+ e. b8 Tmon in girls than in boys.1,3 Most boys with CPP
9 U! [3 d3 e( f% h* }may have a central nervous system lesion that is
: s( A- m* L1 l$ B; b" i' Qresponsible for the early activation of the hypothal-4 C( h. X+ q8 _' W7 ?* S7 z
amic pituitary gonadal axis.1-3 Thus, greater empha-+ j8 N0 X/ q6 W  @: x  l
sis has been given to neuroradiologic imaging in  p8 q$ C9 _4 D
boys with precocious puberty. In addition to viril-. Q$ Q$ d9 n8 F+ \
ization, the clinical hallmark of CPP is the symmet-
0 k" C" o( F- q" p$ {  b7 z, wrical testicular growth secondary to stimulation by* P5 z$ {* x% o" V- H4 }2 X
gonadotropins.1,3
1 d, s0 M) b& k6 U7 x: JGonadotropin-independent peripheral preco-
9 P$ D$ O# n: Z4 t7 X' ?! t& S0 xcious puberty in boys also results from inappropriate- z1 h4 w# m& E; b% T
androgenic stimulation from either endogenous or
6 ?6 A$ |- o! P" O1 b0 A! b0 kexogenous sources, nonpituitary gonadotropin stim-
7 z$ t  G  r* R# U: lulation, and rare activating mutations.3 Virilizing% d" v+ D4 g: Z
congenital adrenal hyperplasia producing excessive2 n' p% r. e3 x/ \+ t
adrenal androgens is a common cause of precocious
6 g1 [+ b" e+ \( {! f# kpuberty in boys.3,4
- K& E5 W# O7 Y- JThe most common form of congenital adrenal3 k. S$ |3 |1 d( A- u
hyperplasia is the 21-hydroxylase enzyme deficiency.
: N0 y  V: o, v! ^) _8 Y( TThe 11-β hydroxylase deficiency may also result in+ l: x5 a8 n9 G: f: V2 P
excessive adrenal androgen production, and rarely,5 b6 J# D; \) z2 h
an adrenal tumor may also cause adrenal androgen. u3 K6 s  ?, u; q# \* @8 c
excess.1,32 |9 P9 x8 f9 y- u
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) ]9 i8 B- S) ]1 \
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
$ F# @; q9 ^, ~' r3 C8 Q. MA unique entity of male-limited gonadotropin-! c4 a( m) ]$ y6 S3 ?. R
independent precocious puberty, which is also known7 f% n3 |5 l5 c$ ?. r
as testotoxicosis, may cause precocious puberty at a
) l7 }5 d' z4 M/ Fvery young age. The physical findings in these boys% {, j- A2 ?: M' {. A
with this disorder are full pubertal development,- n& ^9 Z+ d3 G- a0 I. @' l
including bilateral testicular growth, similar to boys' e' w" C  K' l0 P2 e$ a
with CPP. The gonadotropin levels in this disorder9 {# A3 o4 @- A- o  R4 a
are suppressed to prepubertal levels and do not show
+ Q( N: b! x6 H* E2 epubertal response of gonadotropin after gonadotropin-2 ~+ ~( I. K* `
releasing hormone stimulation. This is a sex-linked' w' H0 R" }4 S
autosomal dominant disorder that affects only* P% U3 M/ m& c/ a: Z1 \. t
males; therefore, other male members of the family0 C- S7 A! a  }. x6 k
may have similar precocious puberty.3' D! F; r- V$ v! Z3 J6 L
In our patient, physical examination was incon-
+ ?  y$ Q' b) u: U2 I8 Msistent with true precocious puberty since his testi-
0 y4 M9 D# P+ i( k6 r- z9 d4 a( `cles were prepubertal in size. However, testotoxicosis+ J* B$ r! A) |& h; z' X* e
was in the differential diagnosis because his father
8 \" K# j9 W+ m+ c- r" lstarted puberty somewhat early, and occasionally,
- o/ r4 ~1 Z0 Z# `) Otesticular enlargement is not that evident in the
2 N7 ]0 F) B3 c( q/ F1 K: M$ Wbeginning of this process.1 In the absence of a neg-
1 c- K0 z- I! }' ]; m: jative initial history of androgen exposure, our  J  B. r2 j2 g* n- _; T
biggest concern was virilizing adrenal hyperplasia,
, c6 m" X3 n1 leither 21-hydroxylase deficiency or 11-β hydroxylase' g7 ^- P; y6 V- l) b
deficiency. Those diagnoses were excluded by find-
& s: Y/ J0 [  Z( C5 King the normal level of adrenal steroids.
6 ^. i. ]# z! vThe diagnosis of exogenous androgens was strongly
1 M/ H6 F2 n8 a7 n( isuspected in a follow-up visit after 4 months because/ o( t" K0 _; s- f3 p" x) [& c; \/ q
the physical examination revealed the complete disap-
# @6 `7 r' Q# Y  w+ ?pearance of pubic hair, normal growth velocity, and% u# B* _5 ?$ A0 H& f
decreased erections. The father admitted using a testos-% D/ Z% Q  q+ Q
terone gel, which he concealed at first visit. He was
6 s0 a9 N2 d* gusing it rather frequently, twice a day. The Physicians’
* S, \  p( P1 ]8 RDesk Reference, or package insert of this product, gel or7 K# B5 t* i* }8 v4 R
cream, cautions about dermal testosterone transfer to
, @$ K& s% r" Q' E7 A. U+ w. Eunprotected females through direct skin exposure.6 s8 O  q6 S0 L: z$ A
Serum testosterone level was found to be 2 times the+ D5 ~. l& w7 _+ K* h+ _# d# B, ^
baseline value in those females who were exposed to
0 `  j! H, R/ y- M6 Veven 15 minutes of direct skin contact with their male
, P' ?4 V6 {: x3 ]# W. Epartners.6 However, when a shirt covered the applica-5 |  u9 V1 u4 Q/ n3 [
tion site, this testosterone transfer was prevented.
, @' q* K% G' P* r- IOur patient’s testosterone level was 60 ng/mL,
. i" E2 S4 W$ [# i  a) N+ Cwhich was clearly high. Some studies suggest that
- \$ O' S  j- A- w. m, D6 k6 h/ f4 Vdermal conversion of testosterone to dihydrotestos-
5 A3 w7 R2 u! f, p, ~+ O4 B6 ~0 Tterone, which is a more potent metabolite, is more1 R: A7 x. l) b& w# Q/ r
active in young children exposed to testosterone
1 M& W' v0 J$ U- O6 xexogenously7; however, we did not measure a dihy-5 H" g7 }* _3 E
drotestosterone level in our patient. In addition to
0 G$ ]1 ~4 |# U0 A( Mvirilization, exposure to exogenous testosterone in
! B2 o7 R& U5 D( y: ?4 _children results in an increase in growth velocity and3 @( E# ]6 U, @; |" c( D) c7 \
advanced bone age, as seen in our patient.4 s& f3 T" b- E+ T
The long-term effect of androgen exposure during/ R' V) o- X. b' W9 y* h
early childhood on pubertal development and final
( C( ]( J% @4 y9 Iadult height are not fully known and always remain
  s* u5 N' X8 s+ U; W, L* Ua concern. Children treated with short-term testos-
, A% f5 t& |7 zterone injection or topical androgen may exhibit some
1 n3 h9 G3 ^/ p) c# f; ~acceleration of the skeletal maturation; however, after! W4 l6 P9 Z# Z1 Y8 w0 L
cessation of treatment, the rate of bone maturation! ?. M: o- ~$ A7 i) x7 O
decelerates and gradually returns to normal.8,9& @/ S5 ^- ]# c0 ]6 n+ f/ g  [
There are conflicting reports and controversy- E$ U2 w( E+ n( W. ~
over the effect of early androgen exposure on adult
3 [( s. z* D4 R, ^6 I! @3 y* jpenile length.10,11 Some reports suggest subnormal
9 T& l) I) y' }  {, r! _adult penile length, apparently because of downreg-) X- `  H4 Z4 y* ^5 j2 ^8 l2 C
ulation of androgen receptor number.10,12 However," L1 o: r' L( g; M1 t* v
Sutherland et al13 did not find a correlation between
& C9 Y$ ?, Z  u: x2 m+ p! V) _  {childhood testosterone exposure and reduced adult
, l) {7 l  e* k/ i, tpenile length in clinical studies.
$ C6 {7 ?$ c/ R3 lNonetheless, we do not believe our patient is
2 Y' M# t0 B* M* m0 l- qgoing to experience any of the untoward effects from
* K1 j5 a. F4 e* ?% Rtestosterone exposure as mentioned earlier because
  ^& ?4 ?, F* ^0 x8 m7 ~' Bthe exposure was not for a prolonged period of time.+ s9 c1 ~! }0 N3 H
Although the bone age was advanced at the time of
$ X  {/ _! g9 S( q* d0 o, P1 f0 |diagnosis, the child had a normal growth velocity at( t4 q% U" t. x2 A  a: n6 v# @" _
the follow-up visit. It is hoped that his final adult
8 c. L" Y+ d8 \height will not be affected.+ I5 X2 B' h' v( ?7 s
Although rarely reported, the widespread avail-( U% [/ k. V9 S, O0 g, u) o3 W7 J
ability of androgen products in our society may6 i7 m) Y& H8 [  j
indeed cause more virilization in male or female: w4 ]3 t6 f8 t2 H) R* ^
children than one would realize. Exposure to andro-: h! {8 S( ?  T& q; O6 Z: a
gen products must be considered and specific ques-
; Z) l3 a3 T: [+ C# {0 `tioning about the use of a testosterone product or
& F3 y) j6 ^: F& Y1 b5 \gel should be asked of the family members during1 y% j% H( B+ Z+ j" V
the evaluation of any children who present with vir-
! o7 L; f) N. x& Z! p8 n3 }ilization or peripheral precocious puberty. The diag-( t  M; o. y7 r8 u
nosis can be established by just a few tests and by0 D% r1 K% f  o9 O% U1 _
appropriate history. The inability to obtain such a
5 K- s; T, q# ~% Mhistory, or failure to ask the specific questions, may
$ V5 p( h1 T4 ]; b. ?" F) ^* e3 ~result in extensive, unnecessary, and expensive
8 L3 v8 ?: _/ n2 Q6 `, z) {# jinvestigation. The primary care physician should be3 Y' V- m& z- V  Z& O0 {
aware of this fact, because most of these children# U! {; z" y0 u1 L
may initially present in their practice. The Physicians’
# m& X+ A8 [$ U. B9 `Desk Reference and package insert should also put a  P4 H" b9 w/ @6 m3 X, v6 Y, }( j
warning about the virilizing effect on a male or
7 s- N3 J- M; g6 Afemale child who might come in contact with some-
, u# }! M# f  ?9 p9 c6 f: e: Z. ^one using any of these products., s; U; I6 }  G) ~5 u$ Q
References
# I- @+ X2 D0 v6 B* e1. Styne DM. The testes: disorder of sexual differentiation
9 i' e6 O) l' K9 D& @and puberty in the male. In: Sperling MA, ed. Pediatric0 J2 y. U9 g, [# Y% A( \* Z* [% }
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
; g4 Q& z# p4 R5 e- L2002: 565-628.
* }3 \8 U7 T! m2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
( f4 z5 E. p1 gpuberty 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 2025-4-8 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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