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Sexual Precocity in a 16-Month-Old3 t. [4 s) n9 Q/ P9 A
Boy Induced by Indirect Topical
; i" ~# g& M$ ZExposure to Testosterone
. `3 k' U# p& Y8 \* cSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
6 Z' v1 C- H$ Z4 P% _+ dand Kenneth R. Rettig, MD1
. ^; Z8 n4 |' o, ]0 i: h3 cClinical Pediatrics
; x: U) Z3 m% N& q: I4 VVolume 46 Number 6
- |$ t$ {# E, X4 N7 N5 p( W8 l$ MJuly 2007 540-543* i. C7 E* P0 H$ D1 w$ _% X
© 2007 Sage Publications5 O$ ~' u1 h6 R; u6 e1 f$ }
10.1177/00099228062966510 [( J8 J: O# |2 g( Y' L9 ^
http://clp.sagepub.com
" F& b! W% S4 v) a" C |* S8 _& [hosted at5 w: _9 t( ?7 q% o% H- G
http://online.sagepub.com, P6 \7 R) l" V& ]% n' [! N7 G
Precocious puberty in boys, central or peripheral,: ]' K, h; x% q' s2 z
is a significant concern for physicians. Central; h1 \2 c3 t2 c. s
precocious puberty (CPP), which is mediated
1 K" r) h& ^$ { bthrough the hypothalamic pituitary gonadal axis, has/ v8 T6 D& s) v1 k& k: K( K
a higher incidence of organic central nervous system) e$ E$ n5 I; W/ H
lesions in boys.1,2 Virilization in boys, as manifested
' m, M6 S9 O) G4 {by enlargement of the penis, development of pubic
# ^7 o ^6 M: ?hair, and facial acne without enlargement of testi-+ g2 j# |1 h0 D6 x% p, |4 J
cles, suggests peripheral or pseudopuberty.1-3 We7 {; ]) @* N- b: l8 _
report a 16-month-old boy who presented with the$ _6 ^+ R1 n2 U
enlargement of the phallus and pubic hair develop-; [ y' s( m' b
ment without testicular enlargement, which was due
, N+ \% g- S1 ]to the unintentional exposure to androgen gel used by2 M K! P3 ~9 {: C. ^1 n' f
the father. The family initially concealed this infor-
$ y) a4 m0 w/ o. H. a& h" d* @mation, resulting in an extensive work-up for this
% O8 z# {1 `9 m% M( Z6 _child. Given the widespread and easy availability of7 {+ h8 e% a' O! B! {
testosterone gel and cream, we believe this is proba-) z. o3 I! n" |, a) S, H
bly more common than the rare case report in the
1 V' ?! l! r. t b7 p- a( L/ }literature.4& E9 L, t3 `+ E6 T& H5 \
Patient Report2 G9 f4 K, z# |& t
A 16-month-old white child was referred to the
8 Y. @ `# U9 e, n6 [- U* Lendocrine clinic by his pediatrician with the concern
2 c1 y0 z. D" s- I" Z. gof early sexual development. His mother noticed
# r, p& ~# s. t+ X" T7 E% T2 flight colored pubic hair development when he was
- {+ i3 _1 M; k0 |From the 1Division of Pediatric Endocrinology, 2University of
" o! F: X" E1 W2 H* y' J0 WSouth Alabama Medical Center, Mobile, Alabama.
% C$ [* V1 `% U" ]5 }' [Address correspondence to: Samar K. Bhowmick, MD, FACE,
; A4 L* f3 n8 x6 E; L7 F( GProfessor of Pediatrics, University of South Alabama, College of
- I1 ^3 J" i A3 tMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;+ O! E$ e# m3 r. d4 O
e-mail: [email protected].( r/ j9 a6 ^5 `- L% a
about 6 to 7 months old, which progressively became) k1 }3 Q8 }' U3 n# V
darker. She was also concerned about the enlarge-" {7 \# k t3 T1 R& f
ment of his penis and frequent erections. The child9 m4 W0 n: q* J* j! @2 f0 k
was the product of a full-term normal delivery, with8 ~- P, ~8 [6 \* U
a birth weight of 7 lb 14 oz, and birth length of
' h! z7 C. h3 B; K2 z( s20 inches. He was breast-fed throughout the first year
' \) f6 A- ?( L/ h0 B. _of life and was still receiving breast milk along with; A- v9 ?/ M- Q9 z! Z- G
solid food. He had no hospitalizations or surgery,
5 x6 W! L2 w4 V) u8 sand his psychosocial and psychomotor development/ u+ ?3 u% `4 o$ u6 |! i' c
was age appropriate.
( o! s% x1 J" p O2 v: nThe family history was remarkable for the father,
3 C2 C/ w( y/ L2 d" }3 Ewho was diagnosed with hypothyroidism at age 16,
6 k/ `& W5 e9 {4 g0 x( b( Kwhich was treated with thyroxine. The father’s
6 a3 M% e2 y4 ^4 E7 ` t0 G, yheight was 6 feet, and he went through a somewhat7 D: q: x$ G4 Q/ R2 k6 I6 W2 b6 ~
early puberty and had stopped growing by age 14.
# p1 W l# y2 c1 w# O0 ~( QThe father denied taking any other medication. The
- M6 T& C: Z# {, K( K( K1 K1 Ochild’s mother was in good health. Her menarche
* v5 I1 D+ \7 [4 k& { Owas at 11 years of age, and her height was at 5 feet5 O; P, P: G! i
5 inches. There was no other family history of pre-
, v5 e" [" V( D2 u/ w' |# @6 Jcocious sexual development in the first-degree rela- ~/ h H/ C o; U) g" p
tives. There were no siblings.3 a. j# k; Z/ n$ l& x% G9 H
Physical Examination3 e1 Y; j& s" |& ]1 i! W1 U- N
The physical examination revealed a very active,# I, C& Y/ N: X
playful, and healthy boy. The vital signs documented
$ H7 o+ Q! ]7 M) R5 P- sa blood pressure of 85/50 mm Hg, his length was
* g9 M0 R1 Y; \* a; q& E9 Z90 cm (>97th percentile), and his weight was 14.4 kg
" K; t U7 O0 n! c/ G8 S(also >97th percentile). The observed yearly growth
- B# u/ `. y" }: kvelocity was 30 cm (12 inches). The examination of
) `+ d0 ~9 j: E6 Lthe neck revealed no thyroid enlargement./ j7 ~0 r# j. w. k
The genitourinary examination was remarkable for4 O- Z+ H- S R2 ^7 q* |
enlargement of the penis, with a stretched length of; E# X; N( W. U- {- y, q
8 cm and a width of 2 cm. The glans penis was very well
! u9 }$ k0 B0 F9 e' K7 P0 udeveloped. The pubic hair was Tanner II, mostly around5 j1 ?; m7 P& P, u n4 P( y7 V
540
" z2 {1 s4 t$ J# Y. _: x! ?1 ]" Vat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% l1 D5 |2 k1 B. B' x
the base of the phallus and was dark and curled. The/ z/ D- Y9 c, A& l f; p
testicular volume was prepubertal at 2 mL each.9 b5 U! R* Z7 t% ?
The skin was moist and smooth and somewhat' L7 p1 |% B. w: o) O0 \+ A
oily. No axillary hair was noted. There were no7 [2 m- n, R( D# \
abnormal skin pigmentations or café-au-lait spots.. m% s7 O$ \; ~4 C' W
Neurologic evaluation showed deep tendon reflex 2+
1 J" `1 [# {' c. y \bilateral and symmetrical. There was no suggestion
6 X5 j3 i) v6 b2 eof papilledema.
! o" i9 ~0 s# r: B: LLaboratory Evaluation6 X; s, V; q( Y4 {: |
The bone age was consistent with 28 months by
1 A0 x% F( a3 _7 A8 Ousing the standard of Greulich and Pyle at a chrono-: e! }" d1 b8 \2 V2 \) c
logic age of 16 months (advanced).5 Chromosomal+ ]+ C5 k& ]& p9 r X9 B* `
karyotype was 46XY. The thyroid function test
2 b. T$ F3 G6 K$ r5 ^showed a free T4 of 1.69 ng/dL, and thyroid stimu-
6 o/ l& h$ A' p) S" N( slating hormone level was 1.3 µIU/mL (both normal). X# E9 Z2 ~& {, Z* ^1 }
The concentrations of serum electrolytes, blood
$ G. k4 `" y2 \5 Y( B# }urea nitrogen, creatinine, and calcium all were
8 J' D% v( }- _ T' swithin normal range for his age. The concentration' ?$ A) f. r z; J* p+ y
of serum 17-hydroxyprogesterone was 16 ng/dL5 z0 ~9 C: c- B! I) ?3 F, Y, }
(normal, 3 to 90 ng/dL), androstenedione was 204 k$ ^4 S3 l3 K4 y
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
$ U( j0 ^- m5 K9 a' Cterone was 38 ng/dL (normal, 50 to 760 ng/dL),
9 T. }4 n# C4 P0 G& y. M. rdesoxycorticosterone was 4.3 ng/dL (normal, 7 to; u) u+ L j+ T m8 ?. F
49ng/dL), 11-desoxycortisol (specific compound S); p) @& m* [* t
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
6 s0 T0 R0 m ?: |5 C; q) jtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total6 [' J, ]/ }% L, |7 M( V) N
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
0 O9 C# `% ^( B. D Wand β-human chorionic gonadotropin was less than# i) j5 K" ]: k6 h
5 mIU/mL (normal <5 mIU/mL). Serum follicular
0 j3 h3 |2 Q" Y7 f1 w+ Wstimulating hormone and leuteinizing hormone5 k; P, v5 L* T: \
concentrations were less than 0.05 mIU/mL
7 N- P& l6 ~ _- \2 P# O+ X! R(prepubertal).9 N8 c J% ?! J6 w: a6 {
The parents were notified about the laboratory
) A/ ^/ M0 |- s* H& C+ vresults and were informed that all of the tests were
3 y6 I* N; x- l% V3 ^6 bnormal except the testosterone level was high. The
- e- P; v6 q1 J1 \6 c6 ofollow-up visit was arranged within a few weeks to# }% x. Z/ |9 o- H) K6 y$ Q/ |
obtain testicular and abdominal sonograms; how-6 l% K2 {. V2 {) U% l
ever, the family did not return for 4 months.; k& z8 s8 r9 m( w: D, {% W9 D
Physical examination at this time revealed that the- o/ K9 ?" A# O, T) a
child had grown 2.5 cm in 4 months and had gained" ]- U7 _' \' g4 {' f
2 kg of weight. Physical examination remained
6 F0 `6 H/ _5 l7 C5 K7 uunchanged. Surprisingly, the pubic hair almost com-% y, B5 f; S3 y" O* d
pletely disappeared except for a few vellous hairs at- R7 A' y6 s( q3 o- I
the base of the phallus. Testicular volume was still 2; H" ?% b& A1 R# q, O
mL, and the size of the penis remained unchanged.
# I$ z3 f; e; t$ d4 YThe mother also said that the boy was no longer hav-
4 p& @. v' u8 {) A# Eing frequent erections.$ ~3 R$ ?3 z8 R* s1 }' V2 H) A
Both parents were again questioned about use of
9 y- Y; O# f8 Eany ointment/creams that they may have applied to7 i. o3 N$ U7 I' N2 g/ {" O
the child’s skin. This time the father admitted the0 F" Q/ e4 j6 ~& r# m
Topical Testosterone Exposure / Bhowmick et al 541( J2 P* b6 I; O" n6 k# h+ g! b; W, s
use of testosterone gel twice daily that he was apply-. d% k. ^- n, n- ~' Y2 h' Z
ing over his own shoulders, chest, and back area for) @5 _( d; m3 F/ R. P) E6 N; N
a year. The father also revealed he was embarrassed% A& T( S% c* @' D. d# K% t
to disclose that he was using a testosterone gel pre-
4 ^3 Q( }6 o% H9 xscribed by his family physician for decreased libido8 X: ?% }/ G, h4 f5 S
secondary to depression.
# c1 j/ o1 P1 I) z- v1 m/ gThe child slept in the same bed with parents.5 h: i f7 w: }7 l6 V
The father would hug the baby and hold him on his
( z' a0 y2 c, a- schest for a considerable period of time, causing sig-
/ a ]& F* r' y- l: r/ F% T: Onificant bare skin contact between baby and father.
7 q+ G( b' `9 S0 o! k6 ?1 PThe father also admitted that after the phone call,
/ x5 q9 @) P3 [when he learned the testosterone level in the baby0 `; S0 B" g9 R( n$ f+ f
was high, he then read the product information
( m% v* d- ^' \; x- o0 G$ spacket and concluded that it was most likely the rea-
7 ~0 C$ ^ ^9 \son for the child’s virilization. At that time, they
0 R5 t/ V$ o" s2 idecided to put the baby in a separate bed, and the* r; H( L, I/ o
father was not hugging him with bare skin and had
; x: P: }# v1 ~% e" n+ u% Fbeen using protective clothing. A repeat testosterone. `. ~; z# s! y( v1 \; b
test was ordered, but the family did not go to the
1 k& i( C; N8 `( y, f& ?laboratory to obtain the test.; s ^- b" S2 w7 m$ B. b$ }/ v5 C9 M: [
Discussion
' R) R8 b0 r" g( C2 e! yPrecocious puberty in boys is defined as secondary
/ h6 {5 E/ r+ t4 F! K/ `sexual development before 9 years of age.1,4# v3 W: |0 F' B/ r
Precocious puberty is termed as central (true) when
# {6 R) k. _, \- cit is caused by the premature activation of hypo-: F% W. S6 i" |6 q3 T! X
thalamic pituitary gonadal axis. CPP is more com-* ~6 y8 J9 H2 Y5 _0 J, D
mon in girls than in boys.1,3 Most boys with CPP0 [* E4 n4 L, U/ G% V$ ?
may have a central nervous system lesion that is
. C9 l& ~2 L0 `" S2 a2 I7 Kresponsible for the early activation of the hypothal-
0 A' X3 S4 I/ u; k. B) ?# L0 A9 ramic pituitary gonadal axis.1-3 Thus, greater empha-+ v7 v) ?) G4 o; p
sis has been given to neuroradiologic imaging in
3 B9 C6 _. ?& R8 K6 L) b) yboys with precocious puberty. In addition to viril-
: {7 Q1 v4 m% T' U' Eization, the clinical hallmark of CPP is the symmet-
4 W; K, _' E5 T. c" |rical testicular growth secondary to stimulation by1 s. M* T' w4 m- F6 W
gonadotropins.1,3
2 Z% B! ]+ A4 t" O" R# t: {Gonadotropin-independent peripheral preco-
A2 g: r. y9 a2 w% I7 U! Q) L! `cious puberty in boys also results from inappropriate
5 V* Z* e8 B+ e% b7 zandrogenic stimulation from either endogenous or; [6 B6 O9 h/ I1 K
exogenous sources, nonpituitary gonadotropin stim-% |8 P7 s: K7 Y
ulation, and rare activating mutations.3 Virilizing
/ ?7 K# @8 ?- B: p% n: `+ Y+ }! Acongenital adrenal hyperplasia producing excessive
) b/ A9 b e2 Qadrenal androgens is a common cause of precocious3 n) J1 M: l7 @
puberty in boys.3,47 A1 Z7 O+ v) u- \9 E1 X
The most common form of congenital adrenal
$ y8 ^% B, R6 B8 hhyperplasia is the 21-hydroxylase enzyme deficiency.
/ P o o6 j0 a5 y: c2 HThe 11-β hydroxylase deficiency may also result in5 d+ k L4 U$ M8 Q6 A( S4 M8 j
excessive adrenal androgen production, and rarely,; H3 B! ], X* t0 t' u
an adrenal tumor may also cause adrenal androgen
: p9 w& P+ h, O8 o: W$ M; g5 T* y6 Fexcess.1,3
1 ~9 q# X. ^: T: ^* ~at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& u5 g! X" |3 _; C6 s- O+ z5 c
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
# J, s* z( c1 _' E4 B8 y" y9 {- k1 hA unique entity of male-limited gonadotropin-
6 G" D! n8 x2 \0 V/ Sindependent precocious puberty, which is also known6 X8 e3 f+ t* I6 s a2 T0 E
as testotoxicosis, may cause precocious puberty at a4 m4 E' C" ?6 O9 l
very young age. The physical findings in these boys
' Z& {, g1 R* ^! J1 p+ k3 uwith this disorder are full pubertal development,2 T" }7 q, ~- ~6 R
including bilateral testicular growth, similar to boys5 D& J, Z9 g6 Y" B& H, b
with CPP. The gonadotropin levels in this disorder
) I& v, U$ U5 f9 W Oare suppressed to prepubertal levels and do not show
0 S" S3 y; o0 L: z- v1 vpubertal response of gonadotropin after gonadotropin-8 {3 a2 l1 U$ ?( H0 m' v* }
releasing hormone stimulation. This is a sex-linked4 c5 G: R; x g7 z' S( k
autosomal dominant disorder that affects only
6 y" _8 {/ v; n m- X3 Smales; therefore, other male members of the family
/ H' X1 s# L* H4 Qmay have similar precocious puberty.36 \0 d" \1 {0 C3 Z ]
In our patient, physical examination was incon-0 h4 d0 d E5 o! @2 C% d
sistent with true precocious puberty since his testi-
% J7 g/ j9 o& o- k9 tcles were prepubertal in size. However, testotoxicosis( r c: e' p$ }
was in the differential diagnosis because his father, q6 E/ s( O0 Z4 {) d: |
started puberty somewhat early, and occasionally,$ X h1 ^$ b" z$ E4 ?: |
testicular enlargement is not that evident in the
7 c. T/ m# s+ I+ D2 ?- ~: Pbeginning of this process.1 In the absence of a neg-
9 w( u) P2 j/ Q% T' P! F$ fative initial history of androgen exposure, our! ]% @, n3 K% X1 M5 z5 j4 q
biggest concern was virilizing adrenal hyperplasia,
" V/ _+ ]. e/ c# S& veither 21-hydroxylase deficiency or 11-β hydroxylase9 Z0 @3 W* n7 m0 a* B
deficiency. Those diagnoses were excluded by find-
' d0 S- j3 G; g/ iing the normal level of adrenal steroids.
" b5 R' M6 e X3 CThe diagnosis of exogenous androgens was strongly! X4 m* b5 j" I
suspected in a follow-up visit after 4 months because
1 x$ w4 X" U4 C5 l# u$ [- ]4 zthe physical examination revealed the complete disap-
|) K0 C6 x! W4 g7 S% s9 hpearance of pubic hair, normal growth velocity, and
7 w! p a1 E+ R; mdecreased erections. The father admitted using a testos-4 D- B( z0 q2 r* @
terone gel, which he concealed at first visit. He was
* j2 J& f, L' j, V/ M/ S! B4 E. \using it rather frequently, twice a day. The Physicians’
; P3 S9 j5 b2 }# a( N$ }+ p# TDesk Reference, or package insert of this product, gel or
: Q9 W6 e# S* C a0 P2 Wcream, cautions about dermal testosterone transfer to! n _' L# \4 @5 ^ Z$ p: t" l
unprotected females through direct skin exposure.
( F- T+ E Q; }5 kSerum testosterone level was found to be 2 times the' I& i* E. @& B- H# q: t
baseline value in those females who were exposed to5 R2 a1 x, N2 w% |, ~
even 15 minutes of direct skin contact with their male* o% |7 ~7 ^( i; N) ]
partners.6 However, when a shirt covered the applica-. l' P3 h) G7 S% P
tion site, this testosterone transfer was prevented.
: o9 w. u! t& W1 v0 f- D* L1 @' N+ nOur patient’s testosterone level was 60 ng/mL,
4 ^3 K' l' o2 ?4 n* }! Z- iwhich was clearly high. Some studies suggest that) u2 S7 Q2 n0 h7 T, W& F1 j
dermal conversion of testosterone to dihydrotestos-7 O+ W* n! s4 O% f
terone, which is a more potent metabolite, is more
9 ^7 b$ G: z* _' \active in young children exposed to testosterone; x- J% f- i" A7 d: e
exogenously7; however, we did not measure a dihy-1 v C" s; Z+ [- j0 W. w/ R# Y; o z
drotestosterone level in our patient. In addition to6 h8 b' K9 ~5 @
virilization, exposure to exogenous testosterone in
& l7 c z4 U% `4 N( o% tchildren results in an increase in growth velocity and8 `: q3 l2 W8 s3 u! s
advanced bone age, as seen in our patient.3 Z1 u! u+ M$ I9 T5 l( |6 }$ c
The long-term effect of androgen exposure during
" Y0 b# T4 h( D* l/ g" K9 H9 q0 Wearly childhood on pubertal development and final
) n' t U- k$ T2 }& vadult height are not fully known and always remain" p7 N7 j" y% i4 u; N
a concern. Children treated with short-term testos-4 K# s @* n& @
terone injection or topical androgen may exhibit some
3 Y& b) L8 d& [# y# kacceleration of the skeletal maturation; however, after
5 e, Z: g7 }5 z7 O2 {1 a& x, zcessation of treatment, the rate of bone maturation
; d" y7 H. k: J7 A. H) Tdecelerates and gradually returns to normal.8,94 |+ A# l0 n+ x, I. h2 c
There are conflicting reports and controversy
I# P$ S3 H4 X- ]/ Yover the effect of early androgen exposure on adult- j+ W5 B5 o" `6 z. o, L. V9 |5 i
penile length.10,11 Some reports suggest subnormal; M% u# y! `! I1 j
adult penile length, apparently because of downreg-6 k. X* q+ Q% L3 y4 D* f
ulation of androgen receptor number.10,12 However,5 m- O; J, z/ ~, r: }2 v* {
Sutherland et al13 did not find a correlation between& e% |) Y5 ^& n9 L! {8 l, w
childhood testosterone exposure and reduced adult
5 H+ s; V5 @ c' Y7 ~penile length in clinical studies.
' }. q8 v% [) m' U' uNonetheless, we do not believe our patient is, ~ G( W4 h( U; h
going to experience any of the untoward effects from( P' c, M4 w' D- {
testosterone exposure as mentioned earlier because
" P4 U' ?9 x& H O, Y( Uthe exposure was not for a prolonged period of time.
, F" W2 x4 ^6 B6 _9 |- R) CAlthough the bone age was advanced at the time of
1 B( M. E% M$ y6 o$ idiagnosis, the child had a normal growth velocity at
3 F8 m% l0 e4 `the follow-up visit. It is hoped that his final adult# [9 R2 `; Q7 s+ r
height will not be affected.) X8 ]2 Z, h4 c5 _! R p8 h
Although rarely reported, the widespread avail-
1 N3 n4 v3 W1 [* i2 v5 y4 e7 d$ rability of androgen products in our society may; I1 G7 O# A! T% {' y0 o
indeed cause more virilization in male or female: Y3 y1 p" K" b5 @. Q6 n
children than one would realize. Exposure to andro-8 f& y1 ?+ R" ~1 c
gen products must be considered and specific ques-8 P; ~ x2 ]" m, ?: _
tioning about the use of a testosterone product or
2 u [5 c+ |+ ^; sgel should be asked of the family members during
- T( u) m7 @6 A; X: ~, O5 uthe evaluation of any children who present with vir-9 A/ h ^9 A" z! t3 u
ilization or peripheral precocious puberty. The diag-
4 k; ~& J4 E* Vnosis can be established by just a few tests and by$ h% w$ l$ g2 V# H! W6 p% ^
appropriate history. The inability to obtain such a( P0 B8 X8 ?" l! j, I$ @' q
history, or failure to ask the specific questions, may/ y4 g# J4 x8 S0 {/ Y# N& L
result in extensive, unnecessary, and expensive
. E; u5 D0 s1 h- jinvestigation. The primary care physician should be- B6 Q" k Q; o
aware of this fact, because most of these children2 B" ?0 ~& g$ @" p" \5 ]. B' i
may initially present in their practice. The Physicians’& K' e( W# }0 i
Desk Reference and package insert should also put a( T) l6 }" ~" N, D8 a$ D0 f# x. q
warning about the virilizing effect on a male or o( ^$ b& Y7 h; J" Q* N
female child who might come in contact with some-
2 ]$ P3 w, k2 Xone using any of these products.
+ [, Y, Q& [; q4 M# gReferences" k0 B: i1 z, V% J6 M
1. Styne DM. The testes: disorder of sexual differentiation
/ R' S( Z7 r7 M5 O6 L# d3 U; u$ `and puberty in the male. In: Sperling MA, ed. Pediatric
/ P) ?2 N2 b0 _Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
8 M9 Y% L, |% C0 m' u) p2002: 565-628.5 _+ K2 g, l8 T& [2 [. }: e
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious" K" F x+ x2 N& {: R
puberty in children with tumours of the suprasellar pineal |
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