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Sexual Precocity in a 16-Month-Old8 c! [8 s) A }5 R
Boy Induced by Indirect Topical: W. M( ^; @: e q" n, f% w+ z
Exposure to Testosterone
I, \" J# F ~0 \" ^Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
; B6 U% Y( }/ O# `+ rand Kenneth R. Rettig, MD1
' v- d' K4 O+ s0 Q) q4 PClinical Pediatrics
% @& `% H; T4 ^7 j- O; l1 MVolume 46 Number 6
, o G2 V3 o" F! n( |7 m2 P9 MJuly 2007 540-543% m& {& b* C$ g+ h
© 2007 Sage Publications
" o$ \/ x: y( d0 z( D, L10.1177/0009922806296651
, k0 @* J9 K& U8 Q1 T% E, Xhttp://clp.sagepub.com; D- h% y; m) b/ L3 t5 B2 C$ O4 l
hosted at
7 k( P; w4 c) b2 W5 R9 n4 f( Q! [! Ohttp://online.sagepub.com' X, t1 i+ @% e5 t H6 H4 K4 G$ C) g
Precocious puberty in boys, central or peripheral,
! _8 N% Q7 k6 d* o+ O, Fis a significant concern for physicians. Central( I; l1 o' l3 l" I; n5 c
precocious puberty (CPP), which is mediated
+ r8 G' |3 A, E* ?4 p- {- u( lthrough the hypothalamic pituitary gonadal axis, has
% {) j8 I4 e: t5 Da higher incidence of organic central nervous system
8 ?+ J, z( E6 c* e; A/ ~lesions in boys.1,2 Virilization in boys, as manifested
9 v, `3 @! c! b0 ~) _, Y9 |by enlargement of the penis, development of pubic
$ W U1 c. w5 J3 vhair, and facial acne without enlargement of testi-
) K. }" b6 m" g4 Hcles, suggests peripheral or pseudopuberty.1-3 We* g: b# L% S+ l0 k( `# y+ o
report a 16-month-old boy who presented with the D) f: Y) C& o9 u) K
enlargement of the phallus and pubic hair develop-
8 Y" U8 j, d+ s7 z( x |ment without testicular enlargement, which was due
/ ^9 s- o, L% n2 u- L# N' a* X$ ato the unintentional exposure to androgen gel used by
' E" n6 ]& l( m4 C: X% bthe father. The family initially concealed this infor-
/ `* [' Q8 {- Lmation, resulting in an extensive work-up for this
$ w0 @6 E3 x+ ~& n" uchild. Given the widespread and easy availability of
( q9 D C7 E! M- K6 s$ ?" C7 Btestosterone gel and cream, we believe this is proba-
) S, c5 z' }, u- Z4 H& J# a1 Obly more common than the rare case report in the
; Z; G7 d1 E% k" x; ?literature.4
4 p4 S) H5 {& x. f- T$ b) h6 [Patient Report( |& X, f. F1 C7 J2 ]% o* W
A 16-month-old white child was referred to the1 T3 h5 X$ d) p4 \1 Y" R! p
endocrine clinic by his pediatrician with the concern" B& E8 ~0 j+ s! w& d
of early sexual development. His mother noticed
, M. `' h* q1 K: r- glight colored pubic hair development when he was
3 T! e# Y, a u4 g* S" N' W2 P2 {From the 1Division of Pediatric Endocrinology, 2University of# A' a/ @$ K& H! B
South Alabama Medical Center, Mobile, Alabama./ K6 {4 T& P8 L; Z0 `, H
Address correspondence to: Samar K. Bhowmick, MD, FACE,
; M1 y3 }8 X4 X; {1 G; b- LProfessor of Pediatrics, University of South Alabama, College of
+ [8 d; b4 f& eMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
) i9 `6 t! U3 r q4 ce-mail: [email protected].( A$ I. q* P* f$ h; _+ Z
about 6 to 7 months old, which progressively became" V' d. S A8 S& @
darker. She was also concerned about the enlarge-6 O. N- r% Q4 N
ment of his penis and frequent erections. The child
8 v9 U) U( C0 b. Z. Mwas the product of a full-term normal delivery, with* h, S# C/ R' u9 ~: R; C- ~$ F2 \! Q0 u
a birth weight of 7 lb 14 oz, and birth length of
4 G: E) F) _4 m20 inches. He was breast-fed throughout the first year7 m7 c: e& P& y Q& K1 ~ h
of life and was still receiving breast milk along with- B2 c+ i2 Q7 j
solid food. He had no hospitalizations or surgery,
8 O+ P8 T6 x$ w7 I5 fand his psychosocial and psychomotor development
, r. d+ ]: c* I$ o" n* owas age appropriate.) R) a/ Q# b5 |8 d q; h
The family history was remarkable for the father,
1 |* M5 ]: J* |9 C6 U& Twho was diagnosed with hypothyroidism at age 16,
0 u6 X: w1 X$ @( a! \- V Bwhich was treated with thyroxine. The father’s# r' i- F* K* I" C
height was 6 feet, and he went through a somewhat
: f8 |+ b4 ~# i: L1 Nearly puberty and had stopped growing by age 14.; e# n U0 d( ]4 p; l# Y
The father denied taking any other medication. The0 c+ K% M0 i( }/ X( Q, a
child’s mother was in good health. Her menarche2 v3 r! v) I* s7 V
was at 11 years of age, and her height was at 5 feet# X8 y5 P* k/ A# J& V
5 inches. There was no other family history of pre-
# Y% T" c: T$ E9 J# c, rcocious sexual development in the first-degree rela-
; K6 P5 P/ \6 vtives. There were no siblings.
. `- }/ W5 l6 U" [ S- {9 XPhysical Examination, F# S- K* K9 j( y) {5 W
The physical examination revealed a very active,
4 P$ ], W1 x( q# J# j0 Q i8 Uplayful, and healthy boy. The vital signs documented8 L' B6 n! E$ G! F
a blood pressure of 85/50 mm Hg, his length was
& y3 j" c+ d( w; |( W1 h90 cm (>97th percentile), and his weight was 14.4 kg) a. I# Y _1 {
(also >97th percentile). The observed yearly growth
# D, D( {1 o- F w$ Pvelocity was 30 cm (12 inches). The examination of6 ?: x: j6 F& j* f q$ ~3 a% I" C* V
the neck revealed no thyroid enlargement.
/ e6 B0 V: i' q/ h( Z X" tThe genitourinary examination was remarkable for
# |, ^7 m8 B5 K% H& \enlargement of the penis, with a stretched length of
+ F5 X3 v) |% o }2 Y. e8 cm and a width of 2 cm. The glans penis was very well
, B( L$ F7 {# Ndeveloped. The pubic hair was Tanner II, mostly around% \/ W+ U. U. u, _) S
540
1 F+ s) y2 r& w" `6 n0 Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
) f7 F( I* ~* t1 y' {) D6 _the base of the phallus and was dark and curled. The
9 m& r1 b; l, d$ A' x4 Ptesticular volume was prepubertal at 2 mL each.0 N9 U/ s' X& Z; k+ d* d4 d0 o
The skin was moist and smooth and somewhat, _8 r1 d* I5 P
oily. No axillary hair was noted. There were no/ W7 W0 k7 {1 B8 i7 C6 Q
abnormal skin pigmentations or café-au-lait spots.5 p( I6 `! ~& k! I9 a
Neurologic evaluation showed deep tendon reflex 2+7 ?# `. M' t# n) S3 Q
bilateral and symmetrical. There was no suggestion& m3 G' F0 ^" w$ f5 v
of papilledema.8 k2 w3 F# Y- e, x
Laboratory Evaluation" h, k, G- u- h5 s
The bone age was consistent with 28 months by# a& r3 C/ F8 F- F
using the standard of Greulich and Pyle at a chrono-' R& j8 {2 h) \; w" m' W
logic age of 16 months (advanced).5 Chromosomal
( n- C% p! z, s" b" B* w5 bkaryotype was 46XY. The thyroid function test
( l$ _: `6 `3 d: n7 `$ I9 M/ Nshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
+ N2 b# D B# @' j1 |lating hormone level was 1.3 µIU/mL (both normal).7 W3 b6 W+ n: E5 m" f
The concentrations of serum electrolytes, blood" v* e& i6 X; }! R( E0 \
urea nitrogen, creatinine, and calcium all were
5 W- b4 u' k% m( Owithin normal range for his age. The concentration
! S" w/ T. ^4 s* o% G1 {" ^of serum 17-hydroxyprogesterone was 16 ng/dL
3 C6 _: c4 @, ~; X" ~" A/ l(normal, 3 to 90 ng/dL), androstenedione was 20
0 E" ]7 Q& \$ ?ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-6 ]5 @7 ?% t/ E. p& u
terone was 38 ng/dL (normal, 50 to 760 ng/dL),5 N& T! [) Z* c& w. K, l
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
9 Z% H7 C% d; L" ~49ng/dL), 11-desoxycortisol (specific compound S)
7 \3 f/ K1 r7 o* ~" m8 Swas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor- {6 ?% }# ?% F! k4 ]
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total$ \8 A+ d6 p& \/ N* X: d$ q
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
( j! z2 d! s1 |9 G, [5 u3 ]and β-human chorionic gonadotropin was less than
; y7 Z1 \/ G+ ^; a- l5 mIU/mL (normal <5 mIU/mL). Serum follicular9 ~# P( c% y6 s1 P" C* d' ]
stimulating hormone and leuteinizing hormone
0 r& S6 T; l) n" E& Kconcentrations were less than 0.05 mIU/mL
# U5 h6 q7 @: ]. m(prepubertal).
) r- X W9 s0 Z8 p' W! c: e( eThe parents were notified about the laboratory" W: S6 C! C$ k: D: ]2 }
results and were informed that all of the tests were6 B' @& j' {9 Q7 f
normal except the testosterone level was high. The
8 b( `! i) m; Lfollow-up visit was arranged within a few weeks to* c3 b2 q) c3 Q+ y* F3 s
obtain testicular and abdominal sonograms; how-1 Z4 e* U2 _9 w' Q+ X# m
ever, the family did not return for 4 months.
, D1 ]( o6 O* |( }, zPhysical examination at this time revealed that the
% h. N! Q. H7 _: ^. {" O+ Uchild had grown 2.5 cm in 4 months and had gained
1 k2 q1 p4 h/ D# {0 v9 B2 kg of weight. Physical examination remained2 `. p, a% g2 `& S
unchanged. Surprisingly, the pubic hair almost com-2 Y, I M! d* G3 \2 G; x
pletely disappeared except for a few vellous hairs at
9 ]4 ^$ o# ]+ o" B8 Pthe base of the phallus. Testicular volume was still 2
7 r( L2 i# f. t) r, W# cmL, and the size of the penis remained unchanged.3 c, A5 @& {& \& A
The mother also said that the boy was no longer hav-
9 g/ x7 Q' ~ E5 V- n0 Sing frequent erections." \& b; ?& c+ d3 P9 K
Both parents were again questioned about use of' e+ f0 j2 D. w8 B% H6 i
any ointment/creams that they may have applied to
" ?2 B' h! o% \% mthe child’s skin. This time the father admitted the ]( t$ p* Y! q0 F0 n
Topical Testosterone Exposure / Bhowmick et al 541* j; K# I2 v( ?+ \
use of testosterone gel twice daily that he was apply-9 _* z1 z- z# d: H8 @
ing over his own shoulders, chest, and back area for8 \- ^2 `7 o! J' ]2 J, z% Z
a year. The father also revealed he was embarrassed- D! Y" w/ ?2 E* H8 {, i
to disclose that he was using a testosterone gel pre-# C" T# G) F: _6 x3 q
scribed by his family physician for decreased libido! i9 K1 `3 S2 c" P
secondary to depression.- y$ y" m8 u# A& V0 m
The child slept in the same bed with parents.5 A8 F1 _! ~1 N+ p0 @. h/ i& o, e
The father would hug the baby and hold him on his7 m U" K9 |1 ]$ C' P1 Q- L9 k
chest for a considerable period of time, causing sig-& q: x; p: \$ M; \
nificant bare skin contact between baby and father.
# r+ B3 d. F' E0 s* w, T6 [# @# q+ `The father also admitted that after the phone call,
7 ~1 R" I n' C' C" I6 Lwhen he learned the testosterone level in the baby
9 q" l8 N2 K2 Q: D: b% jwas high, he then read the product information
3 y# Q# }# P# f, \+ Epacket and concluded that it was most likely the rea-
* M7 Z! O4 z* c% M- C' cson for the child’s virilization. At that time, they" [9 B, R5 j3 u- K! H* }* [
decided to put the baby in a separate bed, and the- D, N- C2 e i: }
father was not hugging him with bare skin and had" K, K! q! o7 m: U
been using protective clothing. A repeat testosterone. g8 A% x: }9 E) |, L
test was ordered, but the family did not go to the
/ L7 H1 `4 S o( P! Elaboratory to obtain the test.& j& l! B0 L0 G3 q4 O
Discussion: |0 m3 B0 q8 S$ e5 n
Precocious puberty in boys is defined as secondary' }, D1 [! M7 l! U) W
sexual development before 9 years of age.1,4# t6 F7 m5 o1 `9 f9 G( Z4 y
Precocious puberty is termed as central (true) when, o V+ b2 k5 d' g" G
it is caused by the premature activation of hypo-
7 t9 l& `" @7 W% o: Vthalamic pituitary gonadal axis. CPP is more com-; }3 q4 X7 ]- |
mon in girls than in boys.1,3 Most boys with CPP
# t% R7 [8 f/ E" v' m7 cmay have a central nervous system lesion that is- w7 o, S7 g! ]/ n3 l8 P
responsible for the early activation of the hypothal-5 D- O, m% I% G c
amic pituitary gonadal axis.1-3 Thus, greater empha-& q, j6 v, z0 g; c- T* s
sis has been given to neuroradiologic imaging in
6 h4 \+ c$ w) E8 wboys with precocious puberty. In addition to viril-
- b; x- L: `4 `1 @, Q) b8 Bization, the clinical hallmark of CPP is the symmet-
1 `% j% \! g! N- @* Jrical testicular growth secondary to stimulation by5 S9 p1 `8 z' f0 q" U2 K) Q6 e
gonadotropins.1,3* [+ s. J% [4 R4 U
Gonadotropin-independent peripheral preco-
# W. Z& x+ r) S: {. t3 x. a% Ecious puberty in boys also results from inappropriate
! U5 u4 [6 }# D0 iandrogenic stimulation from either endogenous or: H+ t2 W. L# s, x) B- y, A
exogenous sources, nonpituitary gonadotropin stim-
2 C# B3 Y+ B& [9 t6 yulation, and rare activating mutations.3 Virilizing
) n) y1 |6 U$ c% L" U1 lcongenital adrenal hyperplasia producing excessive
$ N+ V* Z3 s" ]# dadrenal androgens is a common cause of precocious
' z8 x% U1 c8 h0 C: l1 q' d" `puberty in boys.3,4
8 S( I0 B" n. t+ B8 x* ]. P0 GThe most common form of congenital adrenal5 W8 t/ n: ~7 W
hyperplasia is the 21-hydroxylase enzyme deficiency.) y: T r6 e, i' L' t
The 11-β hydroxylase deficiency may also result in
' p2 s& c& @# V8 [$ X' Lexcessive adrenal androgen production, and rarely,
a, v, W+ _. _! L' c) ean adrenal tumor may also cause adrenal androgen8 |0 _( f: J" R# C; y+ M: }' s R
excess.1,34 ~- ?$ {9 F+ a0 p" P0 |( U0 N" a
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% Y8 O7 c: P9 ?9 |% w4 ]3 [3 C
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007- K' M6 R: J/ O5 V) `* u- d5 o
A unique entity of male-limited gonadotropin-
2 A0 H/ c) z$ X" J0 Lindependent precocious puberty, which is also known
8 s- w( h: q4 c4 b8 I! V9 @% eas testotoxicosis, may cause precocious puberty at a
" t% e! P( d7 B( ?/ k5 N$ `0 y7 Y! Svery young age. The physical findings in these boys3 e1 S. A- }3 k3 A; @( c; w
with this disorder are full pubertal development,% C5 k' S9 Q: G7 T8 [+ }
including bilateral testicular growth, similar to boys- ~3 q. z, i+ ~4 _+ u A8 T% ^
with CPP. The gonadotropin levels in this disorder
, i' g7 p1 _ Y# P' T# Hare suppressed to prepubertal levels and do not show; s( A1 m1 S- \# q% ]
pubertal response of gonadotropin after gonadotropin-- Q+ K2 Z7 t" h$ i* e2 n
releasing hormone stimulation. This is a sex-linked
! g9 x- U. r# O- q$ d* I+ u9 \autosomal dominant disorder that affects only, `! W, A+ U: u' v' A) s4 L
males; therefore, other male members of the family. L9 m9 l! @6 O" [
may have similar precocious puberty.36 Y0 j6 `: Y% K/ S6 Z+ D) b
In our patient, physical examination was incon-% M- o9 S* a/ M3 U% A
sistent with true precocious puberty since his testi-
4 G% Z# j* o1 ?; f' kcles were prepubertal in size. However, testotoxicosis! d* h$ [, k" n0 ?! V' c
was in the differential diagnosis because his father, R1 C; {* U; u& Z( |/ U
started puberty somewhat early, and occasionally,
3 D: n% K1 Y6 U! S% j- {6 ktesticular enlargement is not that evident in the0 z; a; V4 ^9 \! a1 p
beginning of this process.1 In the absence of a neg-
/ H! f: \7 A3 [, J4 t* k3 `ative initial history of androgen exposure, our0 m: o7 V0 _* n" O7 J
biggest concern was virilizing adrenal hyperplasia,
- r1 A# b) d3 ]either 21-hydroxylase deficiency or 11-β hydroxylase/ x; e6 ~6 V, t
deficiency. Those diagnoses were excluded by find-/ l+ ~* ~6 n) s8 e/ Y
ing the normal level of adrenal steroids.
' z! A* d9 O' S4 OThe diagnosis of exogenous androgens was strongly
& j# @- `# I9 G) n) z1 q' Rsuspected in a follow-up visit after 4 months because, l& i' v6 o7 n, i6 Y7 |
the physical examination revealed the complete disap-
: p( C7 _* F6 O( U C6 T! Ypearance of pubic hair, normal growth velocity, and0 {4 t0 p- D3 [4 ^$ X
decreased erections. The father admitted using a testos-
/ w4 \* d+ Q$ a! vterone gel, which he concealed at first visit. He was
. X8 l8 C- x* K/ u, I( P! `+ Jusing it rather frequently, twice a day. The Physicians’! A: `( g* X( {- a8 t9 ^" A; W
Desk Reference, or package insert of this product, gel or
' \# d- h4 W; x& Ycream, cautions about dermal testosterone transfer to
: V' ` v* |, D5 {unprotected females through direct skin exposure.
* Y' ?- p/ z5 V s! C1 c$ rSerum testosterone level was found to be 2 times the. [: H5 u. k- U* g
baseline value in those females who were exposed to8 w8 {4 r; o, n" R9 V f
even 15 minutes of direct skin contact with their male& r( J1 W, a( K: x4 O0 x/ T
partners.6 However, when a shirt covered the applica-
# ?6 Y) \3 J+ U+ u( `6 t0 [tion site, this testosterone transfer was prevented.5 [6 r( H$ }7 S m* v5 e
Our patient’s testosterone level was 60 ng/mL, I0 T- O+ l* L0 O
which was clearly high. Some studies suggest that! z$ F& j7 d( q: _2 l* f) O
dermal conversion of testosterone to dihydrotestos-- [1 S. @% B. e9 o0 p
terone, which is a more potent metabolite, is more
- F1 Y/ R% q" D( Qactive in young children exposed to testosterone9 T, q. P9 f3 m+ ~. k
exogenously7; however, we did not measure a dihy-: M6 r1 ?" z; R3 J
drotestosterone level in our patient. In addition to0 @2 V: O: G# m5 E7 F/ _/ v
virilization, exposure to exogenous testosterone in& q& m) [0 J8 [+ F: O' E1 _" z
children results in an increase in growth velocity and
3 D% q' n" t* ]* Y$ [advanced bone age, as seen in our patient.+ i3 z8 ^0 i) {" V7 g( V% ?8 I
The long-term effect of androgen exposure during
d$ K, U/ k$ w) b8 w( n* F+ zearly childhood on pubertal development and final5 X% C; n0 o5 c/ a" I8 S& n8 d+ s( k
adult height are not fully known and always remain# H9 J7 f. W2 {% D8 \0 z1 W
a concern. Children treated with short-term testos-
; y, G7 x" d8 ^" rterone injection or topical androgen may exhibit some( o, c9 P B1 M' o' i J5 k
acceleration of the skeletal maturation; however, after5 Y ~6 N5 @, U: Y# k
cessation of treatment, the rate of bone maturation, r% V* Q( m" E# o6 L
decelerates and gradually returns to normal.8,92 O X/ g `" a5 w$ X M3 |
There are conflicting reports and controversy
! A9 C6 W8 Q$ Z# U8 Z l8 [over the effect of early androgen exposure on adult9 [; m* v' a N4 \! i! f3 h
penile length.10,11 Some reports suggest subnormal4 b1 @$ n0 `9 W, J2 V; U3 g. J
adult penile length, apparently because of downreg-: ]% H/ g- X6 e, v) x9 C; M
ulation of androgen receptor number.10,12 However,
2 \0 m4 t3 |2 ISutherland et al13 did not find a correlation between
W8 z: D* R4 C2 C1 K }9 z+ M. K Schildhood testosterone exposure and reduced adult# J0 E& x; B4 N' n
penile length in clinical studies.. y3 v9 S: I4 `+ ?1 @
Nonetheless, we do not believe our patient is
' A9 J: M1 U+ ?$ V1 wgoing to experience any of the untoward effects from
* [. i; C6 Q3 P: c: p0 ~testosterone exposure as mentioned earlier because3 _) b3 r$ | x( O# ^
the exposure was not for a prolonged period of time.
. Y/ y# Z1 n9 R/ JAlthough the bone age was advanced at the time of
6 ^# A/ G s+ t5 w/ Hdiagnosis, the child had a normal growth velocity at
" T; Q& Y# \0 s! [2 uthe follow-up visit. It is hoped that his final adult. H, A, p n0 R/ d3 s- [/ ~
height will not be affected.
5 o- P0 q: b2 jAlthough rarely reported, the widespread avail-
5 y; ^2 ?) l b1 sability of androgen products in our society may9 D8 J( E7 d E. r2 c' w* O2 n
indeed cause more virilization in male or female: b! W* H5 O& i5 A7 Q: J2 N
children than one would realize. Exposure to andro-' v4 D/ m- c: f0 `/ N: e
gen products must be considered and specific ques-
: a E- k5 N+ v, ationing about the use of a testosterone product or9 T1 S' k+ r6 O, m
gel should be asked of the family members during' b( g( x% l8 B3 o! b' V
the evaluation of any children who present with vir-9 o1 c% w. t' i2 [0 I
ilization or peripheral precocious puberty. The diag-
8 ?; J, u; s6 v0 Lnosis can be established by just a few tests and by
! H X N' H! vappropriate history. The inability to obtain such a0 X7 c' V8 a8 @ v j1 l
history, or failure to ask the specific questions, may
$ J4 I. w$ Y7 t& q% \) @result in extensive, unnecessary, and expensive
- r$ \0 h R3 Z* @5 O, D& Cinvestigation. The primary care physician should be
S/ V$ |( t) Y! Caware of this fact, because most of these children
" A# x. j* l. U) \may initially present in their practice. The Physicians’
p$ q6 I1 U! e# nDesk Reference and package insert should also put a
9 ^/ t) a/ D1 n) N7 `3 ^- k# Swarning about the virilizing effect on a male or- q8 ^" }9 ~. w3 A3 Q
female child who might come in contact with some-" F% W7 `: @4 G2 F9 ?
one using any of these products.: T% E. |8 g$ N {: G/ o9 q2 {
References
& k7 @2 }; x1 z( {1. Styne DM. The testes: disorder of sexual differentiation
/ v% k2 }4 B* D0 x1 ^and puberty in the male. In: Sperling MA, ed. Pediatric
2 q2 t# q1 {4 L$ N A! ~Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% e. g7 e$ ]& j- f3 K
2002: 565-628.
, b% U/ i% i7 |% @4 V: A4 d$ z2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious& g2 z* h1 X# [) E
puberty in children with tumours of the suprasellar pineal |
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