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Sexual Precocity in a 16-Month-Old( t- V; X7 P8 o
Boy Induced by Indirect Topical0 q% ~* D/ v+ V4 S$ Z: `
Exposure to Testosterone
% F* y( v- X: P" rSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
1 v( f6 p8 y' Y5 c8 k# ]and Kenneth R. Rettig, MD17 n/ c* e8 m5 K. ^$ U" T
Clinical Pediatrics9 e0 S5 C" q0 ?% d. t6 z
Volume 46 Number 6
8 U B% ~$ r. v) T, }July 2007 540-5437 {+ N$ o. p3 L- N
© 2007 Sage Publications x1 x5 ~/ V% J
10.1177/0009922806296651
% V. J) Y* ], w' x) ~http://clp.sagepub.com
8 u' p- ]- P( xhosted at5 a# B) v- R' u$ l6 g1 [1 I
http://online.sagepub.com1 O5 }/ `( @" a& A* u/ h' `
Precocious puberty in boys, central or peripheral,% H0 r$ d2 Y# _& L3 E' e" @. m2 e
is a significant concern for physicians. Central* ^1 h6 W9 L# T$ e
precocious puberty (CPP), which is mediated
4 A2 k# V6 S" k/ S( l. ythrough the hypothalamic pituitary gonadal axis, has
+ G n' H- ?! I* @" ^a higher incidence of organic central nervous system- u+ r8 T9 e( d8 m6 i5 x% E
lesions in boys.1,2 Virilization in boys, as manifested
6 M9 U; I. s- N! @6 r7 Kby enlargement of the penis, development of pubic8 V: Q4 ]# N5 K& H3 _
hair, and facial acne without enlargement of testi-: r; e( _' L7 r$ K% G& L o
cles, suggests peripheral or pseudopuberty.1-3 We1 R1 r% F; w" T Y8 Q5 Z7 u
report a 16-month-old boy who presented with the
$ |! i! k; @; I+ T9 g9 menlargement of the phallus and pubic hair develop-) ~1 R- m- V" m5 E& I6 B/ u( ^
ment without testicular enlargement, which was due
6 R' a/ e& J8 q7 X0 ?& ?- y- N# Sto the unintentional exposure to androgen gel used by+ x( N1 \4 T% {6 m9 P/ V- k; y
the father. The family initially concealed this infor-
0 y$ L- G! [" P- f2 Y; g/ y& gmation, resulting in an extensive work-up for this9 d7 X$ B0 ]( P6 c
child. Given the widespread and easy availability of
# l9 U# m2 g0 @/ ?7 @- P; d" O! C, n8 ztestosterone gel and cream, we believe this is proba-+ V! Z1 l+ I% x0 e
bly more common than the rare case report in the, T1 z8 j0 O! t( |2 d
literature.4: k2 b2 [( p6 M9 m% Y# X
Patient Report7 Q$ @4 M" E% k U+ C' ?' y$ R' _
A 16-month-old white child was referred to the
4 \8 h* v- |6 O o/ z" T! P! lendocrine clinic by his pediatrician with the concern+ \ ~, V- V# I' t
of early sexual development. His mother noticed
- ]: ?" x' a1 C. D2 ?- [" G- rlight colored pubic hair development when he was2 q+ r* k3 z. H5 j! \
From the 1Division of Pediatric Endocrinology, 2University of7 |0 Y# a V# ~2 ^' f8 z- M
South Alabama Medical Center, Mobile, Alabama.5 A1 t4 ]& Z$ P
Address correspondence to: Samar K. Bhowmick, MD, FACE,+ {3 x, a' v7 |, j# \0 ^
Professor of Pediatrics, University of South Alabama, College of
# m* i1 m, @/ E" k( u: ~Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;1 a! ?% A3 R) f9 K
e-mail: [email protected].
% t6 u( Q1 i, Jabout 6 to 7 months old, which progressively became! I1 U2 A, K" u7 x
darker. She was also concerned about the enlarge-, T: |/ b8 t! }6 g6 n8 b2 Z- U
ment of his penis and frequent erections. The child$ m P" ]; ^8 S$ C
was the product of a full-term normal delivery, with
u" n) w3 d6 V6 o6 ~; x9 Y; ca birth weight of 7 lb 14 oz, and birth length of
. r1 @ g! Y } i6 v; _20 inches. He was breast-fed throughout the first year+ b; L+ r1 r+ a5 V V
of life and was still receiving breast milk along with
6 l- s$ b9 \+ \# h+ f1 qsolid food. He had no hospitalizations or surgery,9 r9 T) W7 ^) n: q6 X& A
and his psychosocial and psychomotor development
+ L4 i' r/ [$ ?4 _& S" ~was age appropriate. `5 l. T) B+ v8 w' V
The family history was remarkable for the father,' C [7 ^/ h. T6 Q, Q
who was diagnosed with hypothyroidism at age 16,3 |# N1 N* p2 }4 h
which was treated with thyroxine. The father’s% e2 h" K2 C$ X3 e# f* G# F
height was 6 feet, and he went through a somewhat2 M% G! D& o+ x5 a
early puberty and had stopped growing by age 14.) t4 l. G/ E1 ]
The father denied taking any other medication. The
. S3 M2 \; r5 mchild’s mother was in good health. Her menarche7 w. L5 O# n1 \; E$ _
was at 11 years of age, and her height was at 5 feet% R. ?" D; R" M( \4 m$ E8 _
5 inches. There was no other family history of pre-" n6 s9 a. l7 ?1 D
cocious sexual development in the first-degree rela-
4 ]1 [. f( i! m9 Ztives. There were no siblings.& K, D$ i5 t* B$ j* Y0 q4 n5 l
Physical Examination
; J$ P3 N8 `& u0 AThe physical examination revealed a very active,' I1 F V4 H( P% j
playful, and healthy boy. The vital signs documented" k# {4 x9 b/ {" x
a blood pressure of 85/50 mm Hg, his length was6 N1 w+ \* v2 B7 T
90 cm (>97th percentile), and his weight was 14.4 kg+ B* b$ D1 H) ^' ]+ |
(also >97th percentile). The observed yearly growth2 \9 Q$ {$ j+ J& s
velocity was 30 cm (12 inches). The examination of: ?/ q- s: P! o
the neck revealed no thyroid enlargement.1 ^6 T5 a% d1 z# x
The genitourinary examination was remarkable for! K- w2 C- d8 ^* o
enlargement of the penis, with a stretched length of J* A) O: A9 `' { g
8 cm and a width of 2 cm. The glans penis was very well( A; ~2 ^: [) S5 f! q9 i. f
developed. The pubic hair was Tanner II, mostly around9 r) u5 b. d4 s
540
5 ^' m0 {. Z2 B( K8 eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 M- ]+ Q/ M, L$ _& E7 l3 h3 ythe base of the phallus and was dark and curled. The4 A8 A* y1 C( _, }
testicular volume was prepubertal at 2 mL each.- _! t _" e$ Z0 ?9 B( J! l) y& D: E
The skin was moist and smooth and somewhat
7 {( |, x* M' eoily. No axillary hair was noted. There were no
$ F0 v, o0 p+ _9 h5 ^ Vabnormal skin pigmentations or café-au-lait spots.
) M3 @" p0 s. p% [5 wNeurologic evaluation showed deep tendon reflex 2+
. D& p6 [& J# P; D4 E, F& I1 Kbilateral and symmetrical. There was no suggestion
/ }# ^. H8 v( g$ P; c; m$ S1 |of papilledema.
- b; u: a( K5 S2 p) jLaboratory Evaluation
5 V% e! q2 g: wThe bone age was consistent with 28 months by
" {. I5 N4 Q! \; |- M( Pusing the standard of Greulich and Pyle at a chrono-% x5 V% r4 H& D) D2 ]
logic age of 16 months (advanced).5 Chromosomal
- m: J$ V: h# A. ^( hkaryotype was 46XY. The thyroid function test
6 z7 H3 X& b( R7 zshowed a free T4 of 1.69 ng/dL, and thyroid stimu-8 w; a' S' `+ {6 R
lating hormone level was 1.3 µIU/mL (both normal).9 _& E2 r- c X3 B6 M- g, P$ C& o- x
The concentrations of serum electrolytes, blood! t# j1 |1 h4 h- ], G
urea nitrogen, creatinine, and calcium all were
1 p$ z0 v6 s6 J# z0 x& [within normal range for his age. The concentration
9 q- W+ T2 n3 @0 I! k# U# Tof serum 17-hydroxyprogesterone was 16 ng/dL: a5 n, D4 a. L1 N
(normal, 3 to 90 ng/dL), androstenedione was 20
7 a& q7 T5 n. ?( cng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
( V; ~) t; l4 `: c& F2 P/ o* hterone was 38 ng/dL (normal, 50 to 760 ng/dL),: C" \; @ p7 I8 T0 T" }, q. w. ~$ P
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
, v% u: K* c( I) q9 r49ng/dL), 11-desoxycortisol (specific compound S)
8 V" Z- R8 [# jwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
) q N& P+ o8 Z- f Q5 Vtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
! K% A' ]3 s# N' D$ ^; c, Jtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),: y2 X2 j6 V& r/ m4 N, s. J
and β-human chorionic gonadotropin was less than" Q9 c. b2 c: }) G2 Y" k6 }/ W# \6 W9 Y
5 mIU/mL (normal <5 mIU/mL). Serum follicular
2 D) M8 v3 ]* V! d6 q) x2 U/ [: xstimulating hormone and leuteinizing hormone3 m5 h. h( f2 Y
concentrations were less than 0.05 mIU/mL
; e5 ~1 h) ?' E1 [' p$ [(prepubertal).
5 p4 s# o3 C2 S; `5 XThe parents were notified about the laboratory
9 [, \" `; Q+ u. e, h( l, }results and were informed that all of the tests were, \" b8 ~0 b$ ]8 _; K" o
normal except the testosterone level was high. The
/ ~; w: z& e8 ]6 p* ?- R; ~follow-up visit was arranged within a few weeks to. I/ l; W+ D( t+ g
obtain testicular and abdominal sonograms; how-
9 [* X# F2 z7 W1 Hever, the family did not return for 4 months.3 F& F7 w+ a% M O5 k e
Physical examination at this time revealed that the
) T* R1 b4 Q8 n; ]& J( t1 nchild had grown 2.5 cm in 4 months and had gained5 a3 f& e4 O, I' p5 n' x. O5 C4 ]) G
2 kg of weight. Physical examination remained: I$ A2 e; A) q0 b$ u9 _
unchanged. Surprisingly, the pubic hair almost com-
+ G. \7 w2 ?" z3 `0 Apletely disappeared except for a few vellous hairs at
/ |5 T1 e K8 b1 C; a w, Lthe base of the phallus. Testicular volume was still 2) D5 e4 l- l: |- [: C
mL, and the size of the penis remained unchanged.
# j9 O, B4 O* w# OThe mother also said that the boy was no longer hav-$ K& g" J, U( |! C: ]
ing frequent erections.; t I# Z2 Z% |0 t: b2 H
Both parents were again questioned about use of
7 j3 V' |6 ?2 }& [' aany ointment/creams that they may have applied to' j8 `1 c# [% A' H
the child’s skin. This time the father admitted the
" g0 N: B1 b. `- L- bTopical Testosterone Exposure / Bhowmick et al 5410 _ V& k' W% a/ A
use of testosterone gel twice daily that he was apply-- `3 d2 X, d( N% V0 W
ing over his own shoulders, chest, and back area for) c. O6 _7 J* }2 m( `' h% i: g' a# g
a year. The father also revealed he was embarrassed$ g1 |9 B: R8 b; X" u$ o, e3 @0 a! E5 h
to disclose that he was using a testosterone gel pre-
) S0 k% t& Z9 z# f# zscribed by his family physician for decreased libido& a- Y2 ~: c& l4 ], _' v1 ?5 i. p
secondary to depression.
" P8 [) T) |2 B- KThe child slept in the same bed with parents.
- c7 r5 Y, W* H. JThe father would hug the baby and hold him on his
1 b* y. }0 S) W5 Uchest for a considerable period of time, causing sig- l7 _+ @# ~1 w4 \3 U
nificant bare skin contact between baby and father.& i& t6 i+ s9 i# J# V' M6 G3 @1 H
The father also admitted that after the phone call,, l: a* o' D7 u! N ?( E
when he learned the testosterone level in the baby
* d. i# y' r9 v Cwas high, he then read the product information1 V! ?/ ?8 J7 k1 u( j
packet and concluded that it was most likely the rea-
" o. W3 @% r( H2 C0 p+ eson for the child’s virilization. At that time, they3 {: H2 ~3 Z0 A$ w r' S
decided to put the baby in a separate bed, and the" ` z2 x" c i1 s& D
father was not hugging him with bare skin and had! m2 x: `$ U9 \
been using protective clothing. A repeat testosterone) e8 y, l y& ]* D1 {: @
test was ordered, but the family did not go to the0 W, g, g3 i9 k' x$ t/ |& x
laboratory to obtain the test.2 }0 S$ F! @; u Q. T! y. o; Y
Discussion+ j) w! d, D' N
Precocious puberty in boys is defined as secondary
" G8 R- a$ i) I; J& ^7 E% csexual development before 9 years of age.1,4. Y& s/ e8 w8 p' w) ^& _
Precocious puberty is termed as central (true) when
$ ]4 a: `6 `# o ?1 o5 O* p- lit is caused by the premature activation of hypo-1 ?! e! B$ {/ X# t
thalamic pituitary gonadal axis. CPP is more com-
/ m% H' }% j0 A, \7 T! b. J' r* tmon in girls than in boys.1,3 Most boys with CPP- p J' l' A3 V3 u2 w$ P
may have a central nervous system lesion that is" ?- t( o% W: H
responsible for the early activation of the hypothal-3 b$ |& y2 u0 A, g) z
amic pituitary gonadal axis.1-3 Thus, greater empha-
% q. O" O. k0 ^sis has been given to neuroradiologic imaging in, E, h) {7 e" h+ [) p0 Y
boys with precocious puberty. In addition to viril-
( p4 c4 {3 S! k0 |# sization, the clinical hallmark of CPP is the symmet- R5 B) K2 N4 _* [7 A5 V
rical testicular growth secondary to stimulation by
$ J: A- y; S0 f2 D% i% Y% o- I Ngonadotropins.1,3; Y+ C# u% }2 w, F1 {
Gonadotropin-independent peripheral preco-
& U5 P, t! O( s& `cious puberty in boys also results from inappropriate
* Z5 k; B4 k5 _6 X5 dandrogenic stimulation from either endogenous or8 \7 P" I% S1 a: m
exogenous sources, nonpituitary gonadotropin stim- p, y# `9 ? s% L% l- Y7 T! x" \
ulation, and rare activating mutations.3 Virilizing2 B5 a2 M3 G4 u9 ^
congenital adrenal hyperplasia producing excessive5 ] ` w! ?. D% Y R
adrenal androgens is a common cause of precocious( t1 q- S" ]2 m. Y% ]! y
puberty in boys.3,4
# y4 f9 n3 C Y* S# \The most common form of congenital adrenal4 T c0 l4 P. o# `0 J4 u
hyperplasia is the 21-hydroxylase enzyme deficiency.2 W. I' [. x1 |8 H, i+ M; [
The 11-β hydroxylase deficiency may also result in
. t5 \. w6 B; R% D% g% F: ]( C/ Cexcessive adrenal androgen production, and rarely,! O. g) r7 ?) ]: I- f/ C
an adrenal tumor may also cause adrenal androgen }& h% D, W* x' Z6 }
excess.1,3* ]9 S# A* u k" p) Z6 N6 R& [
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 U: B7 A( w9 n h8 K542 Clinical Pediatrics / Vol. 46, No. 6, July 20070 g' W. ?4 J$ M% ]5 X6 d4 j& |# c9 ^! r
A unique entity of male-limited gonadotropin-1 }. V" e4 A( _. R
independent precocious puberty, which is also known
9 t8 M0 u k. |5 N- Sas testotoxicosis, may cause precocious puberty at a
/ [ t: r: ~% v/ s/ A: L- Fvery young age. The physical findings in these boys
" c& Q, W# k+ a6 n3 @8 ?with this disorder are full pubertal development,% V8 O5 l. ^; V, C+ K
including bilateral testicular growth, similar to boys
# b4 ~) p8 E$ Q% J( Kwith CPP. The gonadotropin levels in this disorder
, m% A+ L, M" g% S) Xare suppressed to prepubertal levels and do not show( u' L( P: _- l. a F: d# g+ O
pubertal response of gonadotropin after gonadotropin-1 y) b7 t9 Q" y! D! c
releasing hormone stimulation. This is a sex-linked2 R8 A7 C* c" e2 n s
autosomal dominant disorder that affects only
. J# [; G( z7 ymales; therefore, other male members of the family3 G+ z$ m; y9 y4 o. R% Y
may have similar precocious puberty.3
7 s0 |. J0 [9 @$ H* L% h4 jIn our patient, physical examination was incon-$ Z1 E' P, m B0 S! N
sistent with true precocious puberty since his testi-/ J2 ]/ h: C3 c0 b* \/ F k0 [
cles were prepubertal in size. However, testotoxicosis, Y" A7 c3 A( X& n, j' H! z
was in the differential diagnosis because his father# F% p' [( w* H8 f. M$ E3 U& a
started puberty somewhat early, and occasionally,+ G# I; x8 C/ C$ Y5 b6 T
testicular enlargement is not that evident in the& w: q: g/ k" H2 y5 M/ b ^
beginning of this process.1 In the absence of a neg-
. s) y* r- |: Y I5 U5 A9 I7 qative initial history of androgen exposure, our0 R5 M- n* l% u. @/ X* f j' U
biggest concern was virilizing adrenal hyperplasia,, `4 {, b g8 f" K* d
either 21-hydroxylase deficiency or 11-β hydroxylase
! @ `- ^6 w* P1 cdeficiency. Those diagnoses were excluded by find-9 G2 p2 C+ |3 M4 \
ing the normal level of adrenal steroids.5 V$ n! L" a: j4 G( F
The diagnosis of exogenous androgens was strongly5 E* G8 G& g R5 D1 b: P% V
suspected in a follow-up visit after 4 months because/ R) k% F. D& a" W' g3 f" t
the physical examination revealed the complete disap-- @, |# N* v) o
pearance of pubic hair, normal growth velocity, and
" w# v4 S5 c" T- W9 w. D5 E, Tdecreased erections. The father admitted using a testos-
$ W& c2 x7 p! U9 |$ t9 S' Uterone gel, which he concealed at first visit. He was4 E% e& X; e4 }6 l! Y
using it rather frequently, twice a day. The Physicians’0 u, d" b" n) Z2 T' }0 X: P
Desk Reference, or package insert of this product, gel or/ ?" ]3 s7 A- I T/ h+ p( E+ G$ g
cream, cautions about dermal testosterone transfer to
( R' E5 Y; R7 U8 e* o! S8 Cunprotected females through direct skin exposure.
: p0 q* F, s: N* P; a/ [9 }. e& f: iSerum testosterone level was found to be 2 times the
3 T6 n4 F) R' _0 |baseline value in those females who were exposed to
, k, w4 [/ K K0 ceven 15 minutes of direct skin contact with their male
/ Z$ E9 _ E1 i/ r$ ppartners.6 However, when a shirt covered the applica-
& s: B4 X! n. `. P. gtion site, this testosterone transfer was prevented.5 v8 g3 o% v: d3 }' _1 D3 m
Our patient’s testosterone level was 60 ng/mL,: o8 {2 A4 l8 _% {9 y) a" S
which was clearly high. Some studies suggest that
0 U6 r; E( ]) y) M6 T4 ]dermal conversion of testosterone to dihydrotestos-7 S' h/ p. r& u3 L/ Z( D9 x
terone, which is a more potent metabolite, is more7 W9 M( s9 F' m( f
active in young children exposed to testosterone% M; |# G5 ?5 G; @
exogenously7; however, we did not measure a dihy-; |; i: B% _. e
drotestosterone level in our patient. In addition to3 s& X! v% R& s6 q
virilization, exposure to exogenous testosterone in3 G+ ^1 Y; W$ r& n) ` b
children results in an increase in growth velocity and
3 S' w0 X4 z+ D$ J$ _advanced bone age, as seen in our patient.
( ?* p9 j: c2 |8 TThe long-term effect of androgen exposure during* }5 q; b# j9 s7 d5 A- `. j z6 a
early childhood on pubertal development and final1 K; ~# k1 R, s
adult height are not fully known and always remain
8 S4 ^8 D0 f4 }! b% x" @* {a concern. Children treated with short-term testos-0 s/ W% E; s( ~. l4 E2 j! c) I- U6 f
terone injection or topical androgen may exhibit some
+ |, F, U0 |: u1 o. M6 bacceleration of the skeletal maturation; however, after- }: P6 J# v8 s/ |) k; D
cessation of treatment, the rate of bone maturation
! X# Y( c& C& H9 tdecelerates and gradually returns to normal.8,9
, R* P$ ?! q0 {9 A5 ~2 iThere are conflicting reports and controversy
: g' X Y% }3 C- Q, \' vover the effect of early androgen exposure on adult8 W9 k( S1 a7 u& |# }1 l
penile length.10,11 Some reports suggest subnormal
) b- W0 [" S6 Z$ Wadult penile length, apparently because of downreg-7 ^! h: Q: I; {* U$ e. r% ^
ulation of androgen receptor number.10,12 However,
& m9 }' r5 ], F+ }0 W+ s4 k0 PSutherland et al13 did not find a correlation between
! H6 P' r* a- ^, J+ R! ]- q4 d8 Zchildhood testosterone exposure and reduced adult1 ^5 k% A* Y: z: s( ]3 P) D
penile length in clinical studies.2 O$ w% J( a B A1 f$ m" q
Nonetheless, we do not believe our patient is
4 b, M# Q3 }6 w( |* Ogoing to experience any of the untoward effects from
1 R6 u* T1 E. Y, d% k* I Utestosterone exposure as mentioned earlier because! X$ |. M1 [1 m- _; { z
the exposure was not for a prolonged period of time.
; I6 }) c; j1 x, g3 xAlthough the bone age was advanced at the time of" F( a" ^" r, k I" }( i8 \
diagnosis, the child had a normal growth velocity at
! E- P' \/ J/ V/ c% rthe follow-up visit. It is hoped that his final adult G" q3 M% [3 }, k' q1 n* F2 \3 q
height will not be affected.% `# w6 @+ S6 c
Although rarely reported, the widespread avail-
9 X" a& A3 L! {) uability of androgen products in our society may# |2 n! h' e9 V& u G* o/ e8 q
indeed cause more virilization in male or female) h0 \- T2 {: w9 s
children than one would realize. Exposure to andro-8 }3 E* ?! n) K' g, b4 c
gen products must be considered and specific ques- u$ F9 Y ?5 D8 q; h5 W
tioning about the use of a testosterone product or1 e1 p$ X0 M; ^- l3 N: k1 Y
gel should be asked of the family members during
/ ^1 d* V) L- k( S0 |6 \* u% Vthe evaluation of any children who present with vir-
' a q! i4 g: ?% pilization or peripheral precocious puberty. The diag-4 E3 i9 \7 A @- f) Y
nosis can be established by just a few tests and by
/ ^9 O/ @3 Z1 t4 vappropriate history. The inability to obtain such a/ N* a& v S& _$ S
history, or failure to ask the specific questions, may
0 d' J1 r6 @0 g6 sresult in extensive, unnecessary, and expensive
* T5 m' w. c- s. tinvestigation. The primary care physician should be4 _, `: E% Y& \ D, L0 y: K
aware of this fact, because most of these children* g, j! A& a+ g I, v E- s. Z
may initially present in their practice. The Physicians’
0 V5 g) ]% o2 d7 B IDesk Reference and package insert should also put a* ]4 N0 y3 R2 b
warning about the virilizing effect on a male or7 s# ]" S; R L& B; k( R
female child who might come in contact with some-$ o, F* s6 c! R, B
one using any of these products.
/ ~* e$ A* A7 p1 gReferences3 N0 d4 \$ a+ a5 D% G4 j' ^
1. Styne DM. The testes: disorder of sexual differentiation
, _/ j$ I7 I Y* w0 land puberty in the male. In: Sperling MA, ed. Pediatric& e! _" r6 L2 Q: {$ ?
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
- C/ q! i" L* ^. I2002: 565-628.
7 H+ Y/ n/ D3 `) Z2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious5 T ^: X( v2 [0 j0 K( k8 b
puberty in children with tumours of the suprasellar pineal |
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