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Sexual Precocity in a 16-Month-Old
7 w6 I! C7 l, J; ^+ M& @* ?* t$ hBoy Induced by Indirect Topical
+ D% s- [1 P# a' h0 ]Exposure to Testosterone, V: P8 d' g2 O: S
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
& s; g/ s8 y& b6 S; O' D) Jand Kenneth R. Rettig, MD1
/ c& W4 y; g8 c, x0 pClinical Pediatrics; X/ ~! v3 m4 k" X! R7 }
Volume 46 Number 6
1 }: j6 U5 [' S- L% jJuly 2007 540-543
- i' t8 H1 [) Z/ q# w' s© 2007 Sage Publications
) R" n& X: T1 t1 D10.1177/00099228062966516 _( ]) c- W# B
http://clp.sagepub.com) y4 i2 K$ q" V2 u" D3 h7 l
hosted at$ n! S' b) {) ]# y: E- P1 ^
http://online.sagepub.com
v, ^; _4 ^* b- y. mPrecocious puberty in boys, central or peripheral,
0 E' h9 y# n+ U3 ^+ iis a significant concern for physicians. Central3 j8 ]: i9 O6 y+ c# M% y: E+ R
precocious puberty (CPP), which is mediated% D7 d l; ?- v+ P8 Y* h" v
through the hypothalamic pituitary gonadal axis, has" I8 p; b" }0 O T6 n
a higher incidence of organic central nervous system5 v9 [( ~9 Y5 _9 R7 e! \% b, Y" H4 p
lesions in boys.1,2 Virilization in boys, as manifested
6 x( z# `5 ]: a" Xby enlargement of the penis, development of pubic( i8 S; _; H) k, d* ~' m$ d2 k
hair, and facial acne without enlargement of testi-
, o2 H( i1 \/ l, Ccles, suggests peripheral or pseudopuberty.1-3 We3 v0 p/ \" q) r5 d# N4 r
report a 16-month-old boy who presented with the! S. X* ^- P2 L, y! l7 s# a: y
enlargement of the phallus and pubic hair develop-+ Y3 ~* l3 M- ~3 ~5 x7 g9 w$ o+ E
ment without testicular enlargement, which was due6 l6 H7 H6 ]# _1 d7 t( k7 N( C
to the unintentional exposure to androgen gel used by
& u- _: h$ O, y% f: |the father. The family initially concealed this infor-
& x% T- z8 b1 X @mation, resulting in an extensive work-up for this: a5 m: m4 E1 e. S1 t* S
child. Given the widespread and easy availability of
3 p- M5 j% S7 O. m+ ntestosterone gel and cream, we believe this is proba-' j5 \; |2 n x
bly more common than the rare case report in the% _: C# S3 x/ |, i
literature.40 v A' R5 l2 m
Patient Report
: {0 b6 _+ X! L7 n: _A 16-month-old white child was referred to the
* F% t1 q$ \( y' l. M) Xendocrine clinic by his pediatrician with the concern0 E1 L8 {! N& f# F5 H# a
of early sexual development. His mother noticed. ~; n; f7 I" k2 W
light colored pubic hair development when he was7 T O6 C+ C, m6 T$ i
From the 1Division of Pediatric Endocrinology, 2University of9 y) v- \; ]: E$ G- v& c
South Alabama Medical Center, Mobile, Alabama., K/ N g( N1 `& Q# q+ Q
Address correspondence to: Samar K. Bhowmick, MD, FACE,
* Q" u( A @' ]) }; WProfessor of Pediatrics, University of South Alabama, College of
) P/ k F" o5 P) h+ @Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;$ z* F: q# |5 {: ?
e-mail: [email protected].5 j# ^) l5 z5 b9 p* z
about 6 to 7 months old, which progressively became: M/ @ E3 Y: K" ]: p& t
darker. She was also concerned about the enlarge-) ]' O9 T8 E0 z: i5 Z3 S
ment of his penis and frequent erections. The child
/ m, b% u% L" z" x% awas the product of a full-term normal delivery, with
) u P: a. G" N3 d4 Y" }- [a birth weight of 7 lb 14 oz, and birth length of
" Z0 ~" \& t# a" E* ~: p2 M2 \7 D20 inches. He was breast-fed throughout the first year( G9 c/ l# X+ ], z( Z
of life and was still receiving breast milk along with9 \+ _. i1 s8 X( K
solid food. He had no hospitalizations or surgery,% _8 T1 X, Z! \' x' x
and his psychosocial and psychomotor development: a1 S1 N- I0 Z3 z8 i+ j
was age appropriate.
7 @# O' B: k4 c6 G$ M8 v- @( [The family history was remarkable for the father,
, L) u: `7 l& x% m% C( ewho was diagnosed with hypothyroidism at age 16,
+ C- J [" j( ^) m; P; uwhich was treated with thyroxine. The father’s
( G' i4 {8 J! G9 O0 w7 \height was 6 feet, and he went through a somewhat8 o: r( b- @# r, ]; h
early puberty and had stopped growing by age 14.7 o. T8 t t e% h6 [! ?# E
The father denied taking any other medication. The
. O$ N6 M8 h( z% ~5 R: `child’s mother was in good health. Her menarche
/ g& z3 q+ P C2 G& S0 r1 q- J. rwas at 11 years of age, and her height was at 5 feet
" e" l2 {5 t/ L% Q! G5 inches. There was no other family history of pre-+ B# {3 f3 V/ u0 I+ g3 V& c
cocious sexual development in the first-degree rela-
/ q F! a2 A& T, ^$ o' f. h( ftives. There were no siblings.
" O1 |0 q `% FPhysical Examination; P; Q7 |! a' u7 C# z
The physical examination revealed a very active,
+ V' J2 E' x# }# ?0 H! F0 eplayful, and healthy boy. The vital signs documented
! _- c; L5 m, R2 s7 la blood pressure of 85/50 mm Hg, his length was
5 h6 f3 \* F* @7 A4 f90 cm (>97th percentile), and his weight was 14.4 kg7 [3 Q! a2 Y' u1 `
(also >97th percentile). The observed yearly growth1 J9 M& f9 o" y% x1 }! H4 L% \
velocity was 30 cm (12 inches). The examination of: e" g0 t3 M" K1 J" p
the neck revealed no thyroid enlargement.$ V! R, `1 a; B' P a
The genitourinary examination was remarkable for% I' H( p: n' u) d: n
enlargement of the penis, with a stretched length of& x% B6 ~3 K5 H/ P2 P
8 cm and a width of 2 cm. The glans penis was very well
) H; C% ?; d& |8 L1 @" tdeveloped. The pubic hair was Tanner II, mostly around
d6 \+ H9 e$ s; y2 z4 n' K% G540: H R* v$ s+ o" O% b
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from7 N5 g% m% ]+ l; p- o9 |7 n
the base of the phallus and was dark and curled. The
* T* Y+ X9 v) A$ R; ?testicular volume was prepubertal at 2 mL each.) h# x5 ?" d+ l
The skin was moist and smooth and somewhat
( a' F7 B. p5 Y/ ]$ Roily. No axillary hair was noted. There were no) ^1 w) t$ W+ P5 M6 d. F
abnormal skin pigmentations or café-au-lait spots./ H1 `- {$ q+ C" z2 Q3 U4 u
Neurologic evaluation showed deep tendon reflex 2+4 I$ @# N8 a3 j6 V. d, A8 F
bilateral and symmetrical. There was no suggestion, O( J3 {. ^8 n6 K1 g; B
of papilledema.9 _# r; l6 E5 O" v1 v0 F |
Laboratory Evaluation
' `3 |9 Q3 z2 M- B2 lThe bone age was consistent with 28 months by+ M8 ~: p0 ?' {2 h
using the standard of Greulich and Pyle at a chrono-" X% }: o, ^& P! m
logic age of 16 months (advanced).5 Chromosomal- C# b N# e1 a5 } v- |
karyotype was 46XY. The thyroid function test
8 ^' Z ], M/ l6 Q6 Ushowed a free T4 of 1.69 ng/dL, and thyroid stimu-1 A8 X2 z1 ^- ^- `4 W
lating hormone level was 1.3 µIU/mL (both normal).
4 P3 l7 Q! z" e4 \5 }The concentrations of serum electrolytes, blood
6 g4 ]) R$ D4 \urea nitrogen, creatinine, and calcium all were" c; I6 V4 J2 _- B1 i4 e, w
within normal range for his age. The concentration/ k" M; }9 o1 t
of serum 17-hydroxyprogesterone was 16 ng/dL: x' z' ~8 ~3 L1 N" i
(normal, 3 to 90 ng/dL), androstenedione was 20
; B5 h) c; y! ~5 e9 G2 Gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-; E7 W$ J1 w$ f6 ~8 F2 u
terone was 38 ng/dL (normal, 50 to 760 ng/dL),# P' X# G+ N, t C
desoxycorticosterone was 4.3 ng/dL (normal, 7 to: f' H# ^1 g6 B
49ng/dL), 11-desoxycortisol (specific compound S)7 i' h& g8 N0 x7 v5 G9 H8 B1 M
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-4 M* V, i5 X% |- k/ A' v# l1 Y1 M
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
8 @) H" h. J7 w" `testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
0 O5 _( t/ U# o2 tand β-human chorionic gonadotropin was less than
. D4 L/ O: F6 {5 ^; B# N5 mIU/mL (normal <5 mIU/mL). Serum follicular q$ e8 B B' ~1 N
stimulating hormone and leuteinizing hormone
$ E! T# |) [, U6 ], xconcentrations were less than 0.05 mIU/mL( R. ^( a/ J0 o
(prepubertal).
4 Q: [. M& H; M- G1 f+ i% I6 T' ?, ^! `The parents were notified about the laboratory
. y2 ~$ E* F7 Uresults and were informed that all of the tests were
- ]' D' g3 s; g* \3 L+ qnormal except the testosterone level was high. The% y) u" P! w% j [* t- w) \( M2 [
follow-up visit was arranged within a few weeks to1 M8 X" `6 R6 l( H' i7 U' j; X! G
obtain testicular and abdominal sonograms; how-" O( s: \& ^ g& h
ever, the family did not return for 4 months.% m' Q+ r* ?( J- A3 z5 v9 @2 b
Physical examination at this time revealed that the; _2 r: T$ q8 ~# ?' X) J
child had grown 2.5 cm in 4 months and had gained
, [2 `' ]. z: ]. R! i3 f3 O2 kg of weight. Physical examination remained% Y" l! c3 U& U; v: l
unchanged. Surprisingly, the pubic hair almost com-% _* R' W" k% k
pletely disappeared except for a few vellous hairs at
/ p% p+ T" E# G: ^$ Othe base of the phallus. Testicular volume was still 2* o& F. ~" F1 I1 H2 |* {$ U. U8 o2 x0 d; _
mL, and the size of the penis remained unchanged.# b+ t n2 v/ B1 @
The mother also said that the boy was no longer hav-
* H% c' R7 T6 [6 n; ying frequent erections.. o- h7 r! l, n
Both parents were again questioned about use of
- q. U, S$ K1 T# H/ d' R4 @9 vany ointment/creams that they may have applied to
( K' Z `& V2 ?3 Othe child’s skin. This time the father admitted the
+ j% P" D) U. |1 M( z- L* ~$ ATopical Testosterone Exposure / Bhowmick et al 541* C# u9 W. @/ f% \$ ~
use of testosterone gel twice daily that he was apply-
% ]( r6 y4 h y: V$ \3 u# {! ling over his own shoulders, chest, and back area for6 ~+ K6 w/ d6 [* u$ t7 x' X9 n
a year. The father also revealed he was embarrassed3 c" s0 P+ ]; U9 l; k4 h1 l3 d/ z
to disclose that he was using a testosterone gel pre-& r0 P2 l; E6 d, l) j. g D
scribed by his family physician for decreased libido, C% ^$ d4 {" I+ e# `% ~" `
secondary to depression., h# o5 K$ [5 Z, ~& o
The child slept in the same bed with parents.4 ~7 d# m, l: y0 ?+ L; |
The father would hug the baby and hold him on his7 g* M: g% O5 {3 P: V! P
chest for a considerable period of time, causing sig-" o. U* i& s; c2 F
nificant bare skin contact between baby and father.
$ s2 A( W y: Z- kThe father also admitted that after the phone call,( O1 v$ D/ n8 @7 f3 t
when he learned the testosterone level in the baby
5 r _% U J: w) F& p1 q0 Ewas high, he then read the product information
( w; I5 P/ Y9 U4 W- S5 Q* v8 _packet and concluded that it was most likely the rea-
3 S8 c1 {5 ]- d2 f0 T: s7 eson for the child’s virilization. At that time, they# I9 B+ k, `6 H8 P9 l/ ]
decided to put the baby in a separate bed, and the
4 l7 c- c" B! \- k% M& tfather was not hugging him with bare skin and had' v' b3 ~( g* n. N3 A y
been using protective clothing. A repeat testosterone
) B) G8 B) J7 p- e* ttest was ordered, but the family did not go to the
) D, k2 c1 r/ s& llaboratory to obtain the test.+ s- `- W# O2 Y3 g6 V
Discussion8 T, D- z5 y8 r
Precocious puberty in boys is defined as secondary- o5 E o( ~) L2 L
sexual development before 9 years of age.1,4 p# \( C) h$ z: K# j3 A
Precocious puberty is termed as central (true) when; [% j7 t, ?) r8 }8 M5 i
it is caused by the premature activation of hypo-
; |. U: ]4 w7 p; D4 Xthalamic pituitary gonadal axis. CPP is more com-
* g: p4 ~1 D$ H; R, ~9 F- x" gmon in girls than in boys.1,3 Most boys with CPP
$ m2 g& B, Z4 h0 z# N+ tmay have a central nervous system lesion that is
$ ?4 W5 A B$ q, I2 o% x4 y5 z$ | mresponsible for the early activation of the hypothal-' l' J) x4 M# t# H0 h+ F$ [9 |
amic pituitary gonadal axis.1-3 Thus, greater empha-
+ L8 G8 ? ~( w- n' `sis has been given to neuroradiologic imaging in
! O0 M$ [: }+ S3 ]boys with precocious puberty. In addition to viril-0 q8 o8 v5 A7 X5 H6 Q# H
ization, the clinical hallmark of CPP is the symmet-
5 Q/ c D3 o+ a1 ^( f, brical testicular growth secondary to stimulation by
M$ ~2 X1 v7 ygonadotropins.1,3( ]/ D( p& l \& j7 {4 E6 ^
Gonadotropin-independent peripheral preco-
; M6 t9 q! z) J, I$ A% U Hcious puberty in boys also results from inappropriate0 n8 @- g* K* }# Z' E
androgenic stimulation from either endogenous or/ q. r$ H Z6 m6 ^) x4 d
exogenous sources, nonpituitary gonadotropin stim-
3 ]+ T) Q5 N; rulation, and rare activating mutations.3 Virilizing8 s3 S+ @! a7 |& I0 k
congenital adrenal hyperplasia producing excessive$ e+ I1 p+ L' A, {6 L
adrenal androgens is a common cause of precocious& J0 O4 e' K* T) w7 x% {$ \, m2 q
puberty in boys.3,4* L! X; n2 V0 ^% P
The most common form of congenital adrenal4 @. L8 W7 g( x( |6 m1 Z& ]
hyperplasia is the 21-hydroxylase enzyme deficiency." @- K, s, h0 O# W1 B
The 11-β hydroxylase deficiency may also result in
4 y9 L* W2 b5 ?excessive adrenal androgen production, and rarely,) |& Z- h. E; k
an adrenal tumor may also cause adrenal androgen, @' W9 _& N u1 g& o8 g
excess.1,3- P5 s, p- W+ t5 g& b# C
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
|3 u% e9 Q0 [' E) j5 L542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
7 A$ [6 m6 L/ v0 _3 i) ^& z3 y: `0 a5 ZA unique entity of male-limited gonadotropin-/ m/ y% i$ t8 W D& r, A+ C
independent precocious puberty, which is also known
5 x0 p0 F" n, @+ \" {# B4 ?as testotoxicosis, may cause precocious puberty at a$ v! }! o0 r9 c5 H
very young age. The physical findings in these boys
% |& c5 e$ |0 e% v4 v3 Y8 v& ^with this disorder are full pubertal development,3 A8 ?% [7 {% g& u2 b
including bilateral testicular growth, similar to boys' l- j6 F. U6 V8 X
with CPP. The gonadotropin levels in this disorder
8 Q0 c$ A" p3 q, W b! m: \8 S1 hare suppressed to prepubertal levels and do not show$ @2 P* j" Z$ q! o9 p8 D+ G2 w) m
pubertal response of gonadotropin after gonadotropin-; }2 }9 Z' I/ w
releasing hormone stimulation. This is a sex-linked
- X p" V [: H' i6 L9 V% aautosomal dominant disorder that affects only
9 P+ j) F4 ]$ W/ S8 {' g( q) D" L9 G8 imales; therefore, other male members of the family0 s. U0 i5 f+ I5 L; z: N
may have similar precocious puberty.33 } u, k% K+ O$ q! {1 @
In our patient, physical examination was incon-
; _" S/ E" g" T- m9 |sistent with true precocious puberty since his testi-* y4 t7 Q, N# ~0 V
cles were prepubertal in size. However, testotoxicosis) { [% p3 }5 d( K
was in the differential diagnosis because his father
Y) T; O# d& [) ~started puberty somewhat early, and occasionally,7 Q. S: u+ Y& b8 z4 F
testicular enlargement is not that evident in the
2 G1 q0 o1 L2 X" f+ t: o' j. kbeginning of this process.1 In the absence of a neg-; K" ?9 A( o' L" X5 v- m
ative initial history of androgen exposure, our; y( w- d# t7 X( R3 P5 |% |( ~
biggest concern was virilizing adrenal hyperplasia,+ c- Y) h7 E7 ?5 K/ L7 y2 P
either 21-hydroxylase deficiency or 11-β hydroxylase
7 U0 T, t: N. L- W4 ` xdeficiency. Those diagnoses were excluded by find-$ {' s8 E. o; |6 c- N
ing the normal level of adrenal steroids.
2 y. ^5 `6 b* S3 ?The diagnosis of exogenous androgens was strongly
5 k2 R, L/ q& g, X7 a) Q6 u5 z- Lsuspected in a follow-up visit after 4 months because
C+ o$ V R/ g/ C& x. M6 R9 ?the physical examination revealed the complete disap-
: l' [0 c; [2 ~! vpearance of pubic hair, normal growth velocity, and; P' T n, I E- h$ _
decreased erections. The father admitted using a testos-
& Q0 i7 c/ F) {terone gel, which he concealed at first visit. He was
" B: B# N5 I/ R2 l2 Xusing it rather frequently, twice a day. The Physicians’6 q8 d' u0 `! E- E
Desk Reference, or package insert of this product, gel or& |1 ^2 P% y3 \3 W7 B# Q
cream, cautions about dermal testosterone transfer to2 G* B9 A. G$ j5 Z! O3 Y# e$ W+ m
unprotected females through direct skin exposure.& A. v& g8 `! L. v6 Y% @+ }2 p
Serum testosterone level was found to be 2 times the
; _, @% e, h1 {" M- Pbaseline value in those females who were exposed to+ _4 A% F& G' x' `1 n$ i
even 15 minutes of direct skin contact with their male
5 A3 L- q; ^/ X6 dpartners.6 However, when a shirt covered the applica-
/ i0 j* ]) N }, btion site, this testosterone transfer was prevented.
6 m# i7 Z B, s- OOur patient’s testosterone level was 60 ng/mL,
. l! ?5 L% T; e4 \which was clearly high. Some studies suggest that5 `* f) g0 b: }* n8 Z
dermal conversion of testosterone to dihydrotestos-
# W& \3 R( T6 h& u6 sterone, which is a more potent metabolite, is more
( _* W0 w9 o- `% X1 Vactive in young children exposed to testosterone
& u, R, H! Q( m' O3 {( @exogenously7; however, we did not measure a dihy-5 v) {" l) r4 l% ?+ b
drotestosterone level in our patient. In addition to
W3 O+ M! r6 b6 Avirilization, exposure to exogenous testosterone in
, Y7 C; ~) s8 l6 {children results in an increase in growth velocity and
1 p8 d# j! b+ {3 d3 }) e2 padvanced bone age, as seen in our patient.6 S: Y( d- r( W( m+ U
The long-term effect of androgen exposure during
[$ s0 J$ G; @# e% m/ ~' wearly childhood on pubertal development and final( a; O+ [. A& @& K7 Q# A) O
adult height are not fully known and always remain& K; e$ q1 Y% _" V
a concern. Children treated with short-term testos-- [6 \/ ]7 ?0 f! s0 [
terone injection or topical androgen may exhibit some! I! i, b) g6 a+ s/ w5 @
acceleration of the skeletal maturation; however, after/ G5 S+ M5 t" \3 H$ X1 U) U
cessation of treatment, the rate of bone maturation1 }; W& V6 ?* }& B+ G5 o @9 D! N
decelerates and gradually returns to normal.8,9- k/ k; |5 K0 p8 }. C
There are conflicting reports and controversy
p: p3 W9 w# b- C: \: V( W5 lover the effect of early androgen exposure on adult
6 g* D$ A8 X6 p0 L' xpenile length.10,11 Some reports suggest subnormal* X, l8 J' }; |0 B" z. Q
adult penile length, apparently because of downreg-
" Q9 I9 E8 Z( E+ Culation of androgen receptor number.10,12 However,
" |2 j& c8 d% k% s7 d8 }Sutherland et al13 did not find a correlation between% L. k. G v o& h. s1 D Z. D
childhood testosterone exposure and reduced adult
( I7 Y$ n8 I; ~9 _$ N" \penile length in clinical studies.
& \8 z3 e" D% n- K; d% YNonetheless, we do not believe our patient is" l3 j" c: E; ?6 r! w+ G0 D
going to experience any of the untoward effects from
$ c4 p5 J; \! C1 n! S& ntestosterone exposure as mentioned earlier because
/ U2 a7 Q4 u% }$ {" N& P) athe exposure was not for a prolonged period of time.5 y- X" ]5 ^7 \0 t9 c% v; a
Although the bone age was advanced at the time of
6 v+ Z! l3 C W3 Bdiagnosis, the child had a normal growth velocity at5 H8 F/ z! X6 y: V% p7 s3 ^
the follow-up visit. It is hoped that his final adult
- f( d/ ~; u5 X9 `4 q0 B/ v* Gheight will not be affected.) i9 j Z6 z/ g' o' V
Although rarely reported, the widespread avail-8 N' C8 ?0 V2 w: h% L
ability of androgen products in our society may E/ p% n8 [! C8 k8 I( l+ _
indeed cause more virilization in male or female8 R/ B+ k& G( u
children than one would realize. Exposure to andro-
# h% w! g9 w9 T7 F: Qgen products must be considered and specific ques-
6 Y7 _& i9 g4 h6 w' R* [! etioning about the use of a testosterone product or+ }& ?1 r9 ~8 q) u8 I
gel should be asked of the family members during" k: B9 D3 t. l8 h( \
the evaluation of any children who present with vir-
7 i# a1 U1 _$ L# M5 n9 W8 `' }ilization or peripheral precocious puberty. The diag-" I4 `+ G# Q! x8 P; @
nosis can be established by just a few tests and by
- o0 f; L% z( X' ]$ E, i3 iappropriate history. The inability to obtain such a' T2 R9 P% g# W# p v& J
history, or failure to ask the specific questions, may
; N- h" S, v) {9 F. I5 Q0 a( \ [$ \result in extensive, unnecessary, and expensive/ Y9 A1 T6 [) y% ^$ z9 p5 k, |. A
investigation. The primary care physician should be. v/ Z( H9 u0 M
aware of this fact, because most of these children+ [& M- h- N, x8 V, L8 N7 L* W
may initially present in their practice. The Physicians’
0 d5 b% `: E- p" X; C9 ?Desk Reference and package insert should also put a+ A7 g# u2 z. n9 j3 @
warning about the virilizing effect on a male or
- O0 n4 q+ `6 a! O# q+ P0 V( Wfemale child who might come in contact with some-
: N6 B- @/ u' g4 e, P- W8 |: l9 a Mone using any of these products.
* x u! @3 K) [$ ^References1 z# J; B0 N+ g% ?+ _
1. Styne DM. The testes: disorder of sexual differentiation
( U9 i- H8 _+ e d5 wand puberty in the male. In: Sperling MA, ed. Pediatric
, w; k4 x1 R& f3 a# N) K/ s# yEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;" H& B9 Y9 c6 @8 D; k
2002: 565-628.
7 o. n2 Y( t( o7 @! L0 {: a" x3 V2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
: ]' ?' @5 C1 L' `) Y) ]5 Apuberty in children with tumours of the suprasellar pineal |
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