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Mohamed El Kholy , Rasha Tarif Hamza * , Mohamed Saleh and Heba Elsedfy1 n9 I, q) v4 S- p
Penile length and genital anomalies in Egyptian
/ v6 u) w2 G  S# O2 |9 z6 G8 ~male newborns: epidemiology and influence of
9 |) j4 p$ c( a% k" Hendocrine disruptors# o) ]8 P7 E8 n( m$ C, H
Abstract: This is an attempt to establish the normal
  p  Z* c# b' \) G  istretched penile length and prevalence of male geni-. G; u/ }2 @. b8 B) Y! q* ~' h4 F
tal anomalies in full-term neonates and whether they
; s9 [( O/ u8 Q9 R1 Dare influenced by prenatal parental exposure to endo-% S3 i1 R( @( k
crine-disrupting chemicals. A thousand newborns were
/ g! _0 A- i9 p3 Zincluded; their mothers were subjected to the following
- B+ e4 W* ]' B6 wquestionnaire: parents ’ age, residence, occupation, con-
- S2 l: _' I0 x2 Z4 ]0 l  |/ }1 gtact with insecticides and pesticides, antenatal exposure
4 Q3 a3 `. y4 ^  oto cigarette smoke or drugs, family history of genital6 z3 g& w0 a! F1 }3 K4 G: o" P
anomalies, phytoestrogens intake and history of in vitro; W3 g2 P* U# ?2 P; V
fertilization or infertility. Free testosterone was measured
$ l% S6 M: X9 V3 |* u) Q' b6 W. T! @in 150 neonates in the first day of life. Mean penile length
$ f. w4 Q2 h! h0 P4 Nwas 3.4 ± 0.37 cm. A penile length < 2.5 cm was considered- M- |; p# n; G& z: W$ b
micropenis. Prevalence of genital anomalies was 1.8 %
. n4 c7 y  ~  \- {/ j(hypospadias 83.33 % ). There was a higher rate of anoma-3 H! h% R) Q  u* ^: R4 r
lies in those exposed to endocrine disruptors (EDs; 7.4 % )3 I4 L' n& c% t0 o: G+ w" I4 K3 n
than in the non-exposed (1.2 % ; p < 0.0001; odds ratio 6,
3 k* _( e( f' b- Y  |6 E95 % confidence interval 2 – 16). Mean penile length showed0 ^% F& @5 w# W0 I
a linear relationship with free testosterone and was lower; @2 h+ _/ W8 j6 v
in neonates exposed to EDs.
8 s0 R; D; s! \* E+ c- \- j6 r; u  EKeywords: endocrine disruptors; genital anomalies; male;: i6 ]6 j' ^/ i2 H
penile length; testosterone.3 n$ }* E" q( g  N9 X9 G- T
*Corresponding author : Rasha Tarif Hamza, MD, Faculty of
3 z( S5 c6 p$ a/ j! ZMedicine, Department of Pediatrics, Ain Shams University, 361 V! q' `+ A/ a: p2 P- z+ Z
Hisham Labib Street, off Makram Ebeid Street, Nasr City, Cairo
5 S  N0 x: z' N+ J3 m* E2 z11371, Cairo, Egypt, Phone: + 20-2-22734727, Fax: + 20-2-26904430 ,$ I# w/ K) g9 M1 ~
E-mail: [email protected]
% ?! ^/ l  X- {* i( E4 o: P/ jMohamed El Kholy, Mohamed Saleh and Heba Elsedfy: Faculty of% E* u* I- N' t* x
Medicine , Department of Pediatrics, Ain Shams University, Cairo,+ Q$ o. v/ r* |% F
Egypt
: B8 o* G; n1 j" vIntroduction/ o6 ?4 j9 Y1 |/ N, z" x% w* p
Determination of penile size is employed clinically in! x  c+ \4 f# F- C% p2 a: ^' W
the evaluation of children with abnormal genital devel-6 E0 j1 H% |( v6 D# \6 D- G, Q
opment, such as, for example, micropenis, defined as a6 q) `! X( r" D1 L# s: y7 G2 n
penis that is normal in terms of shape and function, but is
2 X0 z8 e9 X- f0 Y# J/ [) i+ smore than 2.5 standard deviations (SD) smaller than mean
- _* {# t9 f2 z: L# @$ \* Msize in terms of length (1) . However, these measurements
( `1 O( A# \8 O* h! T' Lcan be subject to significant international variations, in) B! n4 ^. f7 z" v
addition to being obtained with different methodologies
( d7 L& o; M* i" w2 G( ~, hin some cases (2) .! |3 E' r9 P7 F- \2 h7 |
Over the past 20 years, the documented increase in$ ^- O  \* a9 N7 b1 ?6 X4 s
disorders of male sexual differentiation, such as hypo-
7 ~! ?3 @2 [/ m% mspadias, cryptorchidism, and micropenis, has led to the
7 h* {5 `% U" L+ Osuspicion that environmental chemicals are detrimental
) b9 D0 n+ u, ~4 m, A' eto normal male genital development in utero (3) . The so-
) v# I! a) B" @' d- w5 i4 a) v" |9 Wcalled Sharpe-Skakkebaek hypothesis offered a possible* H' |8 w# e1 H" R8 V
common cause and toxicological mechanism for abnor-
) r/ U/ e2 t8 i! gmalities in men and boys – that is, increased exposure to
; T8 @2 `+ E: A$ z$ [; _oestrogen in utero may interfere with the multiplication  ^; w  d4 k' W) _/ Y
of fetal Sertoli cells, resulting in hormonally mediated
$ z7 ^$ ^* A) h" F; ^developmental effects and, after puberty, reduced quality
* `5 t( g# k. J8 o. \5 N6 m- Aof semen (4) ./ I4 c% C  `7 U2 R- q4 l3 j
It has been proposed that these disorders are part of$ j( N% e6 [& T6 I+ G+ \6 i
a single common underlying entity known as the testicu-9 d0 c# ?6 y4 @& o7 Y6 r& Q" ]
lar dysgenesis syndrome (TDS) (5) . TDS comprises various
2 Z4 w" b$ B& \. c2 K) q  Xaspects of impaired gonadal development and function," e; b. e# a, D7 [; v
including abnormal spermatogenesis, cryptorchidism,) Q- [" `" c" S- g0 }' m
hypospadias, and testicular cancer (6) .
0 y( G. H1 h  R1 l" JThe etiological basis for this condition is complex$ _) v& c1 ?# o: i8 p. K3 z
and is thought to be due to a combination of both genetic
" l& u, E$ f- g# |and environmental factors that result in the disruption
% J, D+ P$ F" N2 u" Bof normal gonadal development during fetal life. First,; n% J  l+ ]9 U3 b/ r* F( U. t
it was proposed that environmental chemicals with oes-; ^4 g6 {$ g) |
trogen-like actions could have adverse effects on male5 `- t- N/ J1 c+ L0 T7 G. g% i
gonadal development. This has since been expanded to
3 m8 z0 P, A+ F9 }, a# g* \5 Jinclude environmental chemicals with anti-androgen, }* H! o9 A2 j
actions and it is now thought that an imbalance between
  {4 v: w. \+ Candrogen and oestrogen activity is the key mechanism by2 ^: y( L% H1 ?3 S* s% U1 H+ G
which exposure to endocrine disrupting chemicals (EDCs)( f* y/ \% j8 K+ f1 ~
results in the development of TDS and male reproductive. v" a6 Z5 K4 e/ x0 l$ o
tract abnormalities (5) .
0 U( N8 @7 p- R+ u# X( x6 ], JWith the increasing use of environmental chemicals,
) g# E( C% ?9 fan attempt was made to establish the normal stretched9 e$ D8 t8 w" `1 p1 r2 x6 X
penile length as well as the prevalence of male genital
2 y9 c' G' l& C( H6 F2 O5 qanomalies in full-term neonates and whether there is an
( P* O1 D: n! ainfluence of prenatal parental exposure to potential EDCs
. {: v. L& V& j8 t; u# [on these parameters.6 j8 Y8 M/ R- J& Q2 R
Brought to you by | University of California - San Francisco
+ ?3 ]/ @7 |) Q1 g+ C2 Q' hAuthenticated$ T( b8 a$ @. M- L/ l
Download Date | 2/18/15 4:26 AM
& c, E3 M& i' d, n510 El Kholy et al.: Penile length and male genital anomalies7 ~) d" J8 r( v
Subjects and methods& t0 x7 |, ?6 Y/ s4 y6 E1 R
Study population5 |. r8 r8 {* H7 i, J! Y) C
The study was conducted as a prospective cohort study at the Univer-8 B: d1 m! ~9 G* [. J
sity Hospital of Ain Shams University, Cairo, Egypt. A sample of 1000
$ R5 v$ |# u1 Z, n  q% T" Xmale full-term newborns was studied.
6 x; H; T# M+ G. k' u0 f# sSampling technique* c$ x/ T$ q$ W- y' {9 j
Three days per week were selected randomly out of 7 days. In each6 g3 T/ v4 r3 ~7 C' Q
day, all male full-term deliveries were selected during the time of fi eld) p2 D( l. }0 S$ O9 k" c  x
study (12 h) during the period from March 2007 to November 2007./ Y! g1 o9 p# x& [; q5 T
Statistical analysis
/ J/ D; R4 D* J: Z2 dThe computer program SPSS for Windows release 11.0 (SPSS Inc.,( c# t0 i7 }2 |( z/ [5 x
Chicago, IL, USA) was used for data entry and analysis. All numeric
/ o0 r# ~( n& q  u2 x3 ?$ p, qvariables were expressed as mean ± SD. Comparison of diff erent vari-. R4 [! Z0 n$ l# D! S
ables between two groups was done using the Student ’ s t-test for4 b. _( H! ~/ P& G$ I7 ]9 L
normally distributed variables. Comparisons of multiple groups were9 V" H; }7 ^6 h, o& L2 K
done using analysis of variance and post hoc tests for normally dis-
1 `7 _8 o6 ]# J; Q# s; H" g# l1 _tributed variables. The χ 2 -test was used to compare the frequency of
/ p2 Z( c" o3 Yqualitative variables among the diff erent groups; the Fisher exact test( E+ _( e- r# D- P6 L- E
was performed in tables containing values < 5. The Pearson correla-% h/ d! p/ S7 o3 o: U1 z6 Z4 x
tion test was used for correlating various variables. For all tests, a
# X2 e; }7 C' C% W1 Q" o& Pprobability (p) < 0.05 was considered signifi cant (10) .) {  N) W. W7 @! p: X; B
Results6 P& H: [6 }9 e. U8 G
Data collected) u2 n# g7 W2 R3 E# K9 L
A researcher completed a structured questionnaire during inter-
$ f: C: N: J  f% \9 Iviews with the mothers. The questionnaire gathered information) c6 r# P' o3 d5 X
on the following: age of parents; residence; occupation of the7 v) w" L4 q  N# {: p, s8 J
parents; contact with insecticides and pesticides and their type and0 B) [+ {. z% o3 l% r" q. T
frequency of contact; maternal exposure to cigarette smoke during
! I4 o. c3 T- z7 P* Spregnancy; maternal drug history during gestation; family history( S  C% |! e+ X- \
of hypospadias, cryptorchidism, or other congenital anomalies; in-9 w( o5 S* Q6 n
take of foods containing phytoestrogens, e.g., soy beans, olive oil,; N, o* s# a: P4 k
garlic, hummus, sesame seed, and their frequency; and, also, his-
" K- V! q4 m' D% Ttory of in vitro fertilization or infertility (type of infertility and drugs' D* e  S+ J9 v8 _2 n$ \; K! n, }
given).
2 u# B" i6 l$ J' ~6 n3 b$ R8 Y1 UEnvironmental exposure to chemicals was evaluated for its po-
4 P  W! {, u/ H8 r" N) N! c# Ttential of causing endocrine disruption. Chemicals were classifi ed
5 q1 ^/ \& F& Z# o: ainto two groups on the basis of scientifi c evidence for their having3 I8 h! [- I5 k% l' e: G: V  B
endocrine-disrupting properties: group I: evidence of endocrine dis-
" I# o8 m. K% f  K6 iruption high and medium exposure concern; group II: no evidence of6 n% D8 O  p* P, R. M) g; P5 ~
endocrine disruption and low exposure concern (7) .
  J/ w8 L1 l$ o# n/ X& p% pDescriptive data) P% f  B) K& C1 A! p+ D; g) l8 O( `
The mean age of newborns ’ fathers was 36 ± 6 years (range
. g2 @( Z& s* Z6 S3 C. J+ \. G20 – 50 years) and that of mothers was 26 ± 5 years (range
1 ?1 j9 Z; h5 S" p" O+ E5 H* \19 – 42 years). Exposure to EDs started long before preg-3 e0 x7 p7 [0 z! K% M9 Q  _  l
nancy and continued throughout pregnancy. Regard-
" A0 |& }$ Q2 i* T3 Y2 ^ing therapeutic history during pregnancy, 99 mothers- G, A7 q  ^& Q) K3 N" e
(9.9 % ) received progestins, 14 (1.4 % ) received insulin,
; {, V9 m) i" |- z6 (0.6 % ) received heparin, 4 (0.04 % ) received long-
5 f( [5 B% G3 Q# U1 @& racting penicillin, 3 (0.3 % ) received aspirin, 2 (0.2 % )' _2 I0 J" Z3 E  }6 j
received B2 agonist, and 1 (0.1 % ) received thyroxin,$ Z8 |1 P7 [6 L
while the rest did not receive any medications during0 Z# l" S% C6 W& x# s
pregnancy except for the known multivitamins and- b" F1 {. |: w- L1 |1 u
calcium supplementations. In addition, family history0 n' a0 q4 W* s. j5 }! O8 D/ B. M
of newborns born small for gestational age was positive7 \6 B4 _( V, O! {, i8 n* z; k) O
in 21 cases (2.1 % ).' Z, C2 x4 a: U$ E6 c
Examination
7 `! t. b! h8 K) z  o1 K1 n; FIn addition to the full examination by the paediatric staff , each boy
9 F% {' k7 w; Y3 Bwas examined for anomalies of the external genitalia during the1 N. [" }* @8 m5 W" _# T% T
fi rst 24 h of life by one specially trained researcher. Examination
6 @! M/ R! T- lof the genital system included measurement of stretched penile3 {/ A7 P3 E5 `, @! t1 B1 e
length (8) and examination of external genitalia for congenital
, K  \! E& Q0 t( i3 Zanomalies such as cryptorchidism (9) and hypospadias. Hypospa-
' h. S7 Z* Y7 g- F8 O, h2 ddias was graded as not glanular, coronal, penile, penoscrotal, scro-
. q, m4 ]# p: k. L6 k; w% xtal, or perineal according to the anatomical position. Cases of iso-( p/ A, J: \. [% ~' G9 p, \
lated malformed foreskin without hypospadias were not included
2 s8 K! o; q! `% eas cases.
6 f3 O4 o( Y! x. e% O2 Q3 f" Q2 oPenile length
! c; k& q7 v4 f9 r& X: p1 I+ mLaboratory investigations8 V  P* Y- I( n1 Z
Free testosterone level was measured in 150 randomly chosen neo-
- o) J6 c2 |8 r1 ]1 Snates from the studied sample in the fi rst day of life (enzyme im-
; W  e( `6 B( r5 n- omunoassay test supplied by Diagnostics Biochem Canada, Inc.,, `' [) i/ g& K% F
Dorchester, Ontario, Canada).  x1 d* v6 y( I* J
Mean penile length was 3.41 ± 0.37 cm (range 2.4 – 4.6 cm).
9 c9 d8 X5 {- |4 F8 s$ B$ K+ SA penile length < 2.5 cm was considered micropenis ( < the6 m% J/ e& Y2 k3 }+ M8 G
mean by 2.5 SD). Two cases (0.2 % ) were considered to/ Q$ o' g1 K! w( r6 N
have micropenis. Mean penile length was lower (p = 0.041)6 J4 d  ~9 v" D) K
in neonates exposed to EDs (n = 81, 3.1 cm) compared to the# N/ U' E: M" W" A3 y
non-exposed group (n = 919, 3.4 cm; Figure 1 ).
6 D: {2 d- N0 g* s3 B8 X" P8 WThere was a linear relationship between penile length
6 W9 Z. q1 o2 S& i; l$ eand the length of the newborn with a regression coef-; G  R* I4 u6 e% A3 A4 l4 \
ficient of 0.05 (95 % CI 0.04 – 0.06; p < 0.0001), i.e., there5 F" p" G, f0 O, a
was an increase of 0.05 cm for each unit increase in length, P$ D! s& \/ j7 k6 e+ m4 T9 ~- ?2 Q
(cm). Similarly, there was a linear relationship between5 j0 \3 e8 E4 Z) d; ^
penile length and the weight of the newborn with a regres-
4 D8 y3 ~+ L' u9 Ysion coefficient of 0.14 (95 % CI 0.09 – 0.18; p < 0.0001), i.e.,, R4 q  ?; A0 w4 \" q
there was an increase of 0.14 cm for each unit increase in1 D9 v$ u. i( h
weight (kg).
/ f6 r( O5 U/ f, w) y' I3 g* Z7 o: HBrought to you by | University of California - San Francisco
: i2 w" C. i  _2 MAuthenticated" K1 R2 q$ O6 L% ?8 s
Download Date | 2/18/15 4:26 AM
1 V* O& Z" ?& K, w" ^El Kholy et al.: Penile length and male genital anomalies 511, [1 z9 G, z$ D6 f
3.456 U& f4 V1 n( o- i  S9 Q
3.40" @  {' ]# M0 O1 ?! J
3.35, o. Q$ }% X: K
3.30
$ k! B& Y9 t4 }3.251 S+ O6 H# X2 s+ L* C- |3 g
3.20( j& M( I/ V, L3 t) }( V' _
3.15
0 G& F2 ]) P0 E+ d. ^3.10
, W( p% F  S5 P9 O3.05
5 N) C6 q- e" I% ^# w! X3.00
" P! n$ \; n8 A9 k! A4 R2.956 T! ]; J. a+ k1 f* }1 w
2.90; t3 y3 K8 Q2 R, I7 C
Mean9 x. p. a8 ^8 D1 J3 U: K
penile, `- ^$ u- h4 ]+ V# D/ Y
length9 D- {! f  Y) c
an odds ratio of 6 (95 % CI 2 – 16), i.e., the exposed persons$ \% \* T# H+ S  O
were six times more likely to develop anomalies than
4 p2 m% c9 C2 p( Sthose not exposed (Table 1 ).
, \0 S$ P& h3 [9 t+ t! u) jGenital anomalies were detected in the offspring
; B; y( [( T2 a0 ^of those exposed to chlorinated hydrocarbons (9.52 % ),7 r' i0 |/ D% v. q/ o
phthalate esters (8.70 % ), and heavy metals (6.25 % ). In$ W6 B8 ^: [" r, e
contrast, none of the newborns exposed to phenols had
% T! Y' y) e( V& U% f" Ugenital anomalies (Table 2 ).
& d8 S6 e; G/ ?1 n: ~' Y" V9 iExposed& ~/ q, ~8 S) w, N: s
Non exposed- h6 D9 r. A8 Q3 [
Penile lengths according to exposure to endocrine
% d5 z- G+ T( rFigure 1 disruptors.
3 ^! t( g! h, S0 ]4 L1 `" `9 j$ wSerum free testosterone levels
) x+ {  z8 n' I$ u) vExposure to cigarette smoke and progestins
7 J+ m2 u5 y9 B! j6 c! |& ^' }- m; cduring the first trimester! i$ i- w7 B% g6 M+ E' w" l1 T
None of the mothers in the study was an active smoker;! X1 R+ U5 @. [1 E& h/ L5 R- L0 @
350 were only exposed through passive smoking. There5 {. d1 j/ J5 ~" C& `" `
was no difference between rates of anomalies among
5 [: \8 n/ ]. j! i+ @$ B& Rthose exposed to cigarette smoke when compared to those' X$ x3 L$ y. i  y6 q
not exposed (1.1 % vs. 2.2 % ). Similarly, there was no differ-! b9 F% f1 l' r2 i
ence between the rates of anomalies among those exposed
+ g# @; h' i4 q- o' \! d; E* [to progestins during the first trimester when compared to
$ o. K, ?! q1 }3 q; w' i! V4 y& X8 ~& Hthe non-exposed ones (2 % vs. 1.8 % ).: Y; ]  d$ q' B& P
In the first day of life, serum free testosterone levels6 U, E$ E9 \+ @# T" ?3 l( G/ i0 d
ranged between 7.2 and 151 pg/mL (mean 61.9 ± 38.4 pg/mL;
' Q) ^1 j3 E: U, Pmedian 60 pg/mL). There was a linear relationship: v! Y7 Q/ i) o& W1 d, L& D
between penile length and testosterone level of the+ H/ J/ |- W0 Q, B& C9 B
newborn with a regression coefficient of 0.002 (95 % CI
/ c8 J: Z& u6 L" R$ e: D% f0.0004 – 0.003; p = 0.01), i.e., there was an increase of 0.2 cm
9 b+ M1 T! c1 i5 x4 Cin penile length per 100 pg/mL increase in testosterone2 o3 ~" G. K! `' t! n! j: A
level. Moreover, serum testosterone level was significantly. m- M9 L- A2 B9 t1 X
lower in newborns exposed to EDs (49.50 ± 22.3 pg/mL)
- S# z! h* R" z) L2 x7 n* Ythan in the non-exposed group (72.20 ± 31.20 pg/mL;
: H1 E9 [6 Q6 h; N1 C. Up < 0.01).
  R& a) R: g- ?$ KTable 1 Frequency of genital anomalies according to type of
& t# l# X; A) e) F* Y( A7 lexposure to endocrine disruptors.
  i4 v: d# N- ^' @+ N; t& QExposure to endocrine& p3 D" \  k0 m6 p' K
disruptors
/ d" |. X2 E6 f* wPrevalence of genital anomalies
: d, l" `$ Z8 k6 @% a3 R  L! dAnomalies Total
& e4 n! d- ]) N8 f$ p9 |Negative Positive
6 \  I8 V% Y: iNegative exposure 908 11 919: U, R' s, @! g+ j
98.8 % 1.2 % 100.0 %* F. p, H# f% S0 |4 a) t
Positive exposure 75 6 81
, D- N+ n1 o" P% F% [92.6 % 7.4 % 100.0 %
1 `2 X9 p8 N1 ^Total 983 17 1000
+ S  m1 v7 Q6 F$ K0 S; s% z98.3 % 1.7 % 100.0 %& L# g  u! T) k* R7 i
χ 2 = 25.05, p < 0.0001.
' Q: c! z9 L+ a/ BOver the study period, the birth prevalence of genital$ ]: W, Y# b2 Y; s5 A3 d$ F2 F
anomalies was 1.8 % , i.e., 18/1000 live birth. Hypospadias
$ r6 |: R! X$ v; K: M+ b% |accounted for 83.33 % of the cases. Fourteen had glanu-& O$ _7 @3 K$ `! `" z/ L8 ^% a
lar hypospadias and one had coronal hypospadias. One& l4 a6 \, V9 o1 v
had penile torsion and another had penile chordee. Right-: ~1 U) m1 u$ m
sided cryptorchidism was present in one newborn./ a  |. j4 t: |: F
Exposure to EDCs) ~' F8 o0 c7 ^8 r7 F: _
Among the whole sample, 81 newborns (8.10 % ) were
& Y0 G2 p  N! w- h# D. ]9 Xexposed to EDs. The duration of exposure varied from( b) T$ e) X" Z+ [3 C" k/ D
2 to 32 years with a frequency of exposure ranging from
- z5 O6 l7 D0 D# S" d# H/ w$ H* bweekly to 2 – 3 months per year.
2 i  N% F% q/ |7 j6 s) qThere was a significantly higher rate of anomalies$ L9 }% i; E& `6 |) O/ _
among those who were exposed to EDs when compared
6 i; b1 z2 Y4 `* j# e! u( p0 Tto non-exposed newborns (7.4 % vs. 1.2 % ; p < 0.0001), with7 P8 ?$ _0 l7 \4 m1 b3 I
Table 2 Type of endocrine disruptor and percentage of anomalies in
0 g6 X; t6 l* a, _) o8 m& Fthe group of neonates exposed to endocrine disruptors (n = 81).
# U0 E* [* I  [, q9 Q# D* sAnomalies Total
! `7 M( J* F- Y/ p9 u* HNegative Positive
9 L( Q) U: m- K1 ZChlorinated hydrocarbons (farmers) 19 2 21# E% n9 t0 c5 s) Q9 q. n, `( A
90.48 % 9.52 % 100.0 %' M9 T# G8 z# N
Heavy metals (iron smiths, welders) 30 2 32
- s. V0 _# {2 t% ~/ h9 J93.75 % 6.25 % 100.0 %! S9 S* J4 E% k; Q
Phthalate esters (house painters) 21 2 23* k/ s9 g) u/ H3 ?
91.30 % 8.70 % 100.0 %
+ B0 |3 \# n# RPhenols (car mechanics) 5 0 5
* D8 `$ F& N0 B% W100.0 % 0 % 100.0 %
* j/ j! b' B, S$ x2 }. e3 ]: @Total 75 6 81
: ^4 ?, Y6 Y1 y0 s, c' D' s8 f, ^' |+ o5 S92.60 % 7.40 % 100.0 %7 m7 e: f$ D7 o
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( ~3 a9 w; ]3 h512 El Kholy et al.: Penile length and male genital anomalies) K+ I" n2 }  J7 F' s
Discussion$ R6 I9 O1 A+ V1 t
Previously reported penile lengths varied from 2.86 to 3.75 cm: C0 O: N5 A  p2 {$ N6 x. N" p
(11 – 16) and depended on ethnicity. In Saudi Arabia (13) ,
$ ]8 ]4 k& l; `; o% y3 O# t6 xmean newborn penile length was 3.55 ± 0.57 cm, slightly' Z0 e+ n. f  K; j1 x6 _; J
higher than our mean value. However, the cut-off lower
8 ^" w. Q1 [% A6 D/ {/ d4 Alimit ( – 2.5 SD) was calculated to be 2.13 cm (vs. 2.5 cm in
9 {- q0 ]$ J& `* qour cohort). This emphasizes the importance of establish-2 b. G- U' e; T6 c/ O
ing the normal values for each country because the normal9 @2 K0 K9 Z4 W# E% p. u# K  `
range could vary markedly. In a multiethnic community,
4 t& Z! H1 a9 m! L& ]- ~a mean length of – 2.5 SD was used for the definition of
5 g1 u. t) o3 K: Q, q& l, W" @2 m: Bmicropenis and was 2.6, 2.5, and 2.3 cm for Caucasian,
& K4 ~8 a7 Z3 ~East-Indian, and Chinese babies, respectively (p < 0.05).- M; B0 c5 y7 H2 y' l
This is close to the widely accepted recommendation that- q8 m' B, m( @/ k1 e2 I3 M
a penile length of 2.4 – 2.5 cm be considered as the lowest
9 {0 a  P  k  X- |limit for the definition of micropenis (8) . The recognition
2 }- y! N0 L% U9 {! a# `of micropenis is important, because it might be the only1 v$ m# h; a* u0 I! B7 [- P& D
obvious manifestation of pituitary or hypothalamic hor-: p5 I- {  z) O( ?! w1 s8 T. _
monal deficiencies (17) .
3 O" x9 r5 w# {+ z0 B; z/ v7 UThe timing for measurement of testosterone in new-
, F0 b3 H& g/ _borns is highly variable but, generally, during the first 21 \4 S7 ]8 \2 r$ }
weeks of life (18) . In our study, serum testosterone level& ^* A3 O) I1 v
was measured in all newborns on day 1 in order to fix a$ [. N" j- _; |& U* t9 @( L8 i
time for sample withdrawal in all newborns and, also, to
' I+ @4 V8 {( M; w$ j! Wmake sure that all samples were withdrawn before mothers
) M6 c4 {% e: P; d+ lwere discharged from the maternity hospital. We found a1 Y5 S4 X% e% {+ `6 u, \" k: y
linear relationship between penile length and testosterone$ k8 Y7 J" \3 F2 j7 S$ Q
levels of newborns. Mean penile length was lower in neo-
) G* ?4 x% e( V9 C1 _  onates exposed to EDs compared to the non-exposed group,- F$ E7 X# {7 f6 I- s
which could be related to the lower testosterone levels in
- o" Y7 W; F3 g# g% }5 Q: wthe exposed group. The etiology of testicular dysgenesis
. d) k/ l) a: jsyndrome (TDS) is suspected to be related to genetic and/or( ]. ]% v, i& y# j* ^' ]  A
environmental factors, including EDs. Few human studies/ f5 `% q$ b* y' u
have found associations/correlations between EDs, includ-- k  D1 l5 H, H5 ^9 H
ing phthalates, and the different TDS components (18) .
+ [0 l& M' N- ~( d; ySome reports have suggested an increase in hypo-
: w, X% I1 v4 A2 ]) [$ @: Rspadias rates during the period 1960 – 1990 in European
/ X3 s5 o. B: }and US registries (19 – 23) . There are large geographical
8 y! K4 T& B+ h4 Udifferences in reported hypospadias rates, ranging from3 x' v3 n  A6 e) z" w
2.0 to 39.7/10,000 live births (23 – 25) . Several explanations
" V7 ]) z) ?' n4 B9 f) m4 nhave been proposed for the increasing trends and geo-
  O- {( y, `  v6 agraphical differences. As male sexual differentiation is  A& v9 h  a* W5 V9 R. \" ~6 S
critically dependent on normal androgen concentrations,
) E: R6 v' a4 v  Fincreased exposure to environmental factors affecting
7 O4 P& Q+ b4 |/ `androgen homeostasis during fetal life (e.g., EDs with* R" l2 z+ Z- `5 T
estrogenic or anti-androgenic properties) may cause
' W, P7 O  r4 }5 a* P5 chypospadias (3, 4) .: D, p$ d6 W) P  u1 \2 {' v
In Western Australia, the average prevalence of hypo-, @7 \9 X' }( m: P9 u4 W
spadias in male infants was 67.7 per 10,000 male births.
* ^/ B9 ^. J; v) RWhen applying the EUROCAT definition (24), the average0 @9 j& D- K; P; i
prevalence of hypospadias during 1980 – 2000 was 21.8 per; [  g. e4 ~5 S& f# {
10,000 births and the average annual prevalence increased
$ C* P9 t3 o3 X# Ssignificantly over the study period by 2.2 % per year. The( ]3 e5 O9 m9 e# X! v- J' c
prevalence of hypospadias in this study was much higher: R5 A: c3 W/ |" }. @
at 150 per 10,000; by excluding glanular hypospadias, the
% P1 M. b3 y( Y8 tprevalence fell sharply to 10 per 10,000 (26) .
; c3 d+ Z# H3 @We found a higher rate of anomalies among newborns
( b. G' \- F5 uexposed to EDs when compared to non-exposed newborns3 k' ^; b& K# |7 z
(7.4 % vs. 1.2 % ); this raises the issue that environmental5 T: G: P$ @5 Z! V
pollution might play a role in causing these anomalies.
% `( q* e& u, `# L' |Within the last decade, several epidemiologic studies# r9 d6 w! |2 J, h1 I5 m
have suggested environmental factors as a possible cause
1 ]: ]/ f% h3 G4 p) _for the observed increased incidence of abnormalities in
$ E5 M* J1 S) ~- ]# Umale reproductive health (27) . Parental environmental/* R$ ^+ K0 S& ^- ?
occupational exposure to EDs before/during pregnancy, s, S) E+ J) _5 ]+ p1 [3 m' G7 M. s
indicates that fetal contamination may be a risk factor for6 Z+ e/ F+ o9 q' I
the development of male external genital malformation" q/ _! K; E6 f. e7 }. I) V, |
(27 – 29) .8 h6 G$ R3 H- n( `1 C
Received October 25, 2012; accepted January 27, 2013; previously4 X" _9 Q2 j* \# L1 r2 W. W
published online March 18, 2013
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El Kholy et al.: Penile length and male genital anomalies 513
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testosterone levels: a longitudinal study of 1962 normal boys., y; c) q4 d; f1 n) ?: m
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of 1040 healthy Turkish children aged 0 to 5 years. Urology
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18. Bay K, Asklund C, Skakkebaek NE, Andersson AM. Testicular
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- {5 E7 w0 j6 b' c19. Czeizel A. Increasing trends in congenital malformations of male6 A( P6 t! L8 E9 J4 G  I8 d" o1 Y& }
external genitalia. Lancet 1985;i:462 – 3.
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 E# b4 x+ |7 P) X1 B9 A  [
GONADOTROPIN. l6 `. ]. m+ b. D0 H6 t9 v) h1 c5 J
RICHARD C. KLUGO* AND JOSEPH C. CERNY1 H' f( C2 j5 }. j2 f" X
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 x: }/ h& D- u8 ]; f3 gABSTRACT
/ M& o8 d5 R; w! wFive patients were treated with gonadotropin and topical testosterone for micropenis associated! J1 {* [) x/ e3 V
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-, O; A( w* P: r9 u2 P6 D# ^! Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 C' |6 @  T/ E9 h; G& @; ^cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent+ W" ?  O4 m3 m& [8 q( F! P
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent* l9 i( I. Q, A) p7 L+ |
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average  k$ y+ F$ A, E) a7 ^9 o) k  E
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response4 \0 d+ [- d' \; m
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, c) F$ q4 Y2 t) W* N; P& e* R3 p$ Rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ \" }  i, r) T. A8 ?9 P9 X
growth. The response appears to be greater in younger children, which is consistent with previ-
( o6 C5 e$ R5 u% B6 h! Z: q( t2 _0 }1 lously published studies of age-related 5 reductase activity.
9 z" h# s+ D9 I4 h$ mChildren with microphallus regardless of its etiology will
2 c1 X, h* E: a) J# d3 Trequire augmentation or consideration for alteration of exter-
: l( x" {& d2 g1 D4 wnal genitalia. In many instances urethroplasty for hypo-
$ ]* v. C; T' k8 r. Tspadias is easier with previous stimulation of phallic growth.( I( e$ O6 A# ^9 `: h
The use of testosterone administered parenterally or topically
$ ?! T1 }) G0 Ohas produced effective phallic growth. 1- 3 The mechanism of/ E- h4 S7 F" G* N: r9 {( o4 p+ U
response has been considered as local or systemic. With this# j3 `4 O: R6 f$ g5 @: t
in mind we studied 5 children with microphallus for response
; p  R0 O( p! H8 _to gonadotropin and to topical testosterone independently.
% a& B4 I% _9 `- j! c9 @: `8 ]MATERIALS AND METHODS4 [2 u7 T* {! r) O4 P
Five 46 XY male subjects between 3 and 17 years old were! l7 h+ g, z+ R' Z1 g7 `
evaluated for serum testosterone levels and hypothalamic9 g' r2 l3 Y, |! ]" i$ L
function. Of these 5 boys 2 were considered to have Kallmann's1 M) g& m7 Q6 t* g" M7 ]
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-3 T' _" a% @/ k
lamic deficiency. After evaluation of response to luteinizing
# v+ r" y# F8 ihormone-releasing hormone these patients were treated with) x, |" M  d2 g* e# g
1,000 units of gonadotropin weekly for 3 weeks. Six weeks! O+ h7 y' Z8 ]' p' g
after completion of gonadotropin therapy 10 per cent topical' I# a0 s% @1 T
testosterone was applied to the phallus twice daily for 3 weeks.
' `4 q( g) j' ?  A5 rSerum testosterone, luteinizing hormone and follicle-stimulat-
/ L& H) M; c0 |+ o; Uing hormone were monitored before, during and after comple-- i. K$ O! R/ Q* [* I/ {
tion of each phase of therapy. Penile stretch length was
% t- e" R$ o) N' [/ q9 j. G  r7 yobtained by measuring from the symphysis pubis to the tip of4 I( ~4 Q; D9 |( h
the glans. Penile circumferential (girth) measurements were
2 P  E( y4 r8 S5 \' V; Sobtained using an orthopedic digital measuring device (see
" w  x- i& `/ i, efigure).
9 L' h) b9 _- o7 jRESULTS$ D' O+ }0 O- P- g3 S
Serum testosterone increased moderately to levels between+ M; U9 p  \; ?& ^1 e0 `
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 b" j; k/ l$ v7 hterone levels with topical testosterone remained near pre-
( `' H6 B7 o. x# d- etreatment levels (35 ng./dl.) or were elevated to similar levels0 a/ ~" \6 r! w7 G, h$ v
developed after gonadotropin therapy (96 ng./dl.). Higher* f0 d* K: A, Y& I  g
serum levels were noted in older patients (12 and 17 years old),
6 `7 X+ z) {% e. I9 x8 Mwhile lower levels persisted in younger patients (4, 8, and 108 K3 [& i3 S9 N2 u& C+ j
years old) (see table). Despite absence of profound alterations
# s' l" v, U2 C, {. K8 `2 @1 b+ O, `of serum testosterone the topical therapy provided a greater
2 }1 e+ a' m! h! N) H0 R; ZAccepted for publication July 1, 1977. ·9 S5 x1 G0 o5 q& c
Read at annual meeting of American Urological Association,
+ n9 a. F1 [/ x6 a* H; \0 J4 }Chicago, Illinois, April 24-28, 1977.
2 X5 |2 S, c; S* D* Requests for reprints: Division of Urology, Henry Ford Hospital,
: t6 F( E- o: H7 e. E2799 W. Grand Blvd., Detroit, Michigan 48202.$ j6 F& D2 V* Y. b2 N! P* \3 E
improvement in phallic growth compared to gonadotropin.
$ t' [4 R+ r  _0 V0 AAverage phallic growth with gonadotropin was 14.3 per cent; ^! _5 m0 N+ `) Y) z( g4 X. ^8 K$ P
increase in length and 5.0 per cent increase of girth. Topical
4 D& d0 ~% n6 A& Vtestosterone produced a 60.0 per cent increase of phallic length
) \! ?  k" [* Q; i* pand 52.9 per cent increase of girth (circumference). The
) k4 g  A1 V9 R  ~' y& F  Aresponse to topical testosterone was greatest in children be-  v, T8 B$ `5 }) k5 |- k
tween 4 and 8 years old, with a gradual decrease to age 17
9 V0 W+ W9 O  U/ Y) F* q+ hyears (see table)." n9 A$ V7 Z+ @* z
DISCUSSION. W. o# x9 z# R1 P. }- @* ]$ Y
Topical testosterone has been used effectively by other
: Y) r+ z( I5 M! n- \7 wclinicians but its mode of action remains controversial. Im-
# z6 o% c, f8 C' L% O2 M  Omergut and associates reported an excellent growth response
3 c, w, Q  c+ H' N) \+ J; }to topical testosterone with low levels of serum testosterone,
7 g7 j9 D$ k9 }! s, R+ `suggesting a local effect.1 Others have obtained growth re-3 t5 j3 [/ t6 |7 _- p3 \
sponse with high. levels of serum testosterone after topical: n9 b5 U. x7 B. u1 ^' R" \
administration, suggesting a systemic response. 3 The use of8 C4 g! T, k7 J
gonadotropin to obtain levels of serum testosterone compara-4 u: ~7 V0 [+ y
ble to levels obtained with topical testosterone would seem to
- P2 @# E, r4 |; H5 p3 aprovide a means to compare the relative effectiveness of- I, J8 \* f0 {6 T* @2 V+ f+ I
topical testosterone to systemic testosterone effect. It cer-! s7 U- w) c! Q8 y" h
tainly has been established that gonadotropin as well as par-) t7 x! I0 f2 {
enteral testosterone administration will produce genital
0 J$ e$ B- R0 z" V. j" b7 T! P0 pgrowth. Our report shows that the growth of the phallus was
; r' }9 B, c# l) qsignificantly greater with topical applications than with go-
1 ^% o0 s  ]! F) r9 e; ]6 ]0 unadotropin, particularly in children less than 10 years old.7 \( U+ _. i4 ~8 ?4 |$ d& X9 w
The levels of serum testosterone remained similar or lower
4 Y& ^( M+ Y1 E' wthan with gonadotropin during therapy, suggesting that topi-9 w) B- y2 y; Z% l
cal application produces genital growth by its local effect as
1 G, l  N; v. i. G+ v% gwell as its systemic effect.
# D' R8 q7 N9 e( E# KReview of our patients and their growth response related to% C* G6 |+ f. d
age shows a greater growth response at an earlier age. This is+ @  V  d8 O- U; U) o! }5 K
consistent with the findings of Wilson and Walker, who+ y( L% i4 z9 ~
reported an increased conversion of testosterone to dihydrotes-
6 h6 J1 _1 j- p; ^. U8 ptosterone in the foreskin of neonates and infants.4 This activ-
3 @; v: [' }" O- {# y0 vity gradually decreases with age until puberty when it ap-
" o+ P3 O  o1 p1 p" Tproaches the same level of activity as peripheral skin. It may0 j! d) Z$ W! R2 s4 l& z
well be that absorption of testosterone is less when applied at
! z; {. M5 X& l. man earlier age as suggested by lower serum levels in children
+ O2 i- p4 P, f% Mless than 10 years old. This fact may be explained by the
7 h) E" s+ u& c  E' [greater ability of phallic skin to convert testosterone to dihy-% E6 T+ d' V' U7 b1 E0 Y4 L
drotestosterone at this age. Conversely, serum levels in older
( t5 M/ v3 ]( Gpatients were higher, possibly because of decreased local& @5 s. v# Z% W( Q2 f( J0 W
667
6 _% Y) }; v+ q* y: C: e1 s1 T' Q668 KLUGO AND CERNY
+ W* v+ y0 C) t+ ~1 D) nPt. Age
! _+ P8 S# j; {(yrs.)
' s2 [3 ?; d$ R6 m) a- a5 R' w6 hSerum Testosterone Phallus (cm.) Change Length+ P% M# ]4 }5 w) I( M1 P- C! R
(ng./dl.) Girth x Length (%); D4 h7 L/ e8 D- p3 {+ ?: C# S+ p) x
4- U  Y! c: z. w. M& W; \$ o, j* h
8
" I% R, V4 E6 P1 B5 z102 g7 m1 _( j* G6 l2 x' ]# @
12
  E4 L. F& K- `( m17
# v9 X0 Q8 h' W: X. i. m- CGonadotropin
2 r6 q( z! G6 e0 l% m71.6 2.0 X 3 16.6' f4 J) i# V! u) M
50.4 4.0 X 5.0 20.0. V9 n# z& t2 C% [& k% q
22.0 4.5 X 4.0 25.02 J: n, a# f) ]5 |  x8 O' {
84.6 4.0 X 4.5 11.1
- z, ^. c/ K# I/ j8 r+ [% K8 q: C, L85.9 4.5 X 5.5 9.0
& K/ s7 c2 G4 N# e9 M3 P/ f% u! pAv. 14.3
. }# m' M* {" T: `% J: q4) h2 E7 O* n" j; k
8
8 i0 C; _0 O, o: B0 H+ M$ S' ?) F101 `9 Z9 Q+ H4 C2 i* B8 i$ l
12
; j2 c( x; q$ I171 w# u8 B& b: m  g
Topical testosterone
- D0 f2 N- @- ^% u3 ]34.6 4.5 X 6.5 850 `( ]1 X9 s. V9 Y9 L
38.8 6.0 X 8.5 708 O5 O; o- Q, y) y
40.0 6.0 X 6.5 62.55 a6 ?  P3 d0 I! N5 t* G' g0 F
93.6 6.0 X 7.0 55.5  U6 \" W4 {# @" i
95.0 6.5 X 7.0 27.2
- l" w) G. [" ~: cAv. 60.0
7 h1 X+ e) ~& u4 c8 V1 ?available testosterone. Again, emphasis should be placed on
2 ~4 K9 p$ ^/ e0 {1 z  |early therapy when lower levels of testosterone appear to4 S: j' M9 T. o8 k8 @& k
provide the best responses. The earlier therapy is instituted5 V( N/ i% R8 c0 |
the more likely there will be an excellent response with low
: ]& j, l4 w; }serum levels. Response occurs throughout adolescence as
) w  w; u2 z$ _8 }. q7 snoted in nomograms of phallic growth. 7 The actual response
9 k* K6 j; d5 f/ N5 S5 o* x* D8 \to a given serum level of testosterone is much greater at birth
0 C4 r$ V9 R9 L4 uand gradually decreases as boys reach puberty. This is most3 H6 y6 C8 b  Q1 M0 v
likely related to the conversion of testosterone to dihydrotes-
! s: U1 c5 r$ ^+ V3 ktosterone and correlates well with the studies of testosterone. x0 \3 T* r: O0 B
conversion in foreskin at various ages.7 u! B& V4 e% h% }
The question arises regarding early treatment as to whether
4 k9 a0 Z4 d. m. {) wone might sacrifice ultimate potential growth as with acceler-$ [/ N+ {- d8 `$ K
ated bone growth. The situation appears quite the reverse% S7 K8 i% D4 a# i' I5 ]  R* q
with phallic response. If the early growth period is not used
# m- M4 \9 _- G6 Vwhen 5a reductase activity is greatest then potential growth
0 L) j' Z$ `& b8 Zmay be lost. We have not observed any regression of growth
# q- Q/ E4 R  Nattained with topical or gonadotropin therapy. It may well
4 m4 z3 }7 |0 c( f" nbe that some patients will show little or no response to any
/ Y% g) P% l( Y/ f. rform of therapy. This would suggest a defect in the ability to
- x6 j8 O# l; U# q3 v6 Pconvert testosterone to dihydrotestosterone and indicate that
0 ?2 c& q) V6 }2 f2 `6 j/ k; |# Uphallic and peripheral skin, and subcutaneous tissue should' y6 j7 M, V7 o1 _! w
be compared for 5a reductase activity.6 W2 m! W" h. ]
A, loop enlarges to measure penile girth in millimeters. B,# P" r  U; g! y. A
example of penile girth computed easily and accurately.: [) l  v- N) p2 P: L+ |* x& S
conversion of testosterone to dihydrotestosterone. It is in this
+ N0 R$ \& t1 [1 V5 F5 Q9 S8 solder group that others have noted high levels of serum
& m+ B7 s) K6 j% O( dtestosterone with topical application. It would also appear
: r) ^7 G" b: z% \. o; ethat phallic response during puberty is related directly to the
2 ?- V3 E) t9 j! a% Yserum testosterone level. There also is other evidence of local4 b. l9 i, @0 Z" i+ G5 O; r
response to testosterone with hair growth and with spermato-
- b6 p% [: r# ?- `& x4 Vgenesis. 5• 6
5 o; B+ p3 ?+ b, s0 j! F; BAdministration of larger doses of gonadotropin or systemic( d* b& A+ {7 N' E1 _# c
testosterone, as well as topical applications that produce
" z( [: i% ~+ K" [9 [& Vhigher levels of serum testosterone (150 to 900 ng./dl.), will
9 [3 X8 h) J( D' h, f( h- talso produce phallic growth but risks accelerated skeletal
4 y8 W% ^% b. G9 d& R/ ?# M; ematuration even after stopping treatment. It would appear
  j7 I- o3 }+ |$ B5 X7 d& M  ithat this may be avoided by topical applications of testosterone
+ w" q6 c# t' k  P# band monitoring of serum testosterone. Even with this control0 j& r7 Z4 L5 Z9 M! ^0 n' k* s0 l
the duration of our therapy did not exceed 3 weeks at any
3 t' g6 k$ N; Q* W4 M+ t0 ftime. It is apparent that the prepuberal male subject may
4 M- W0 }8 F+ Gsuffer accelerated bone growth with testosterone levels near
# M" r) |5 K% D, ^) q; [200 ng./dl. When skeletal maturation is complete the level of, H$ @/ }; z0 Z% B) k
serum testosterone can be maintained in the 700 to 1,300 ng./
; N# S# ~% [5 Y6 r3 [1 Xdl. range to stimulate phallic growth and secondary sexual7 W$ d% t( ?' @- h- J
changes. Therefore, after skeletal maturation parenteral tes-
+ X0 G1 Z  Z& a+ k5 M& _. Mtosterone may be used to advantage. Before skeletal matura-
" [7 n! U% n% v) x) {tion care must be taken to avoid maintaining levels of serum
+ }& u- s- k# G3 r6 d% y4 I( U% s1 dtestosterone more than 100 ng./dl. Low-dose gonadotropin
2 ~% N# _4 p; a$ S- ddepends upon intrinsic testicular activity and may require
2 R, {; b2 }- M  ?* ~prolonged administration for any response.
0 g% s; V' k# PAlternately, topical testosterone does not depend upon tes-% Y1 F9 b' U, I/ n# l8 ^
ticular function and may provide a more constant level of
' ?- s8 K9 b) S( i( \REFERENCES
! l; F+ W9 u  ]! @9 P& U4 U1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# N! _3 R: F4 X, k
R.: The local application of testosterone cream to the prepub-
' j4 _! D2 j4 o: R0 Eertal phallus. J. Urol., 105: 905, 1971.9 b+ b9 t( G) p
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! ^4 A3 Z0 s5 _" |. Etreatment for micropenis during early childhood. J. Pediat.,
) v. z5 I8 a9 L5 [, j: z/ k2 A83: 247, 1973.6 r* n; n/ v% L& E
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* q6 ]# E" ?. k2 L9 V: L* s
one therapy for penile growth. Urology, 6: 708, 1975.# p& Z9 F) M1 G1 q% s+ d8 h* G( \
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 H) f' B& r9 b9 x7 ?2 z2 ]# D( n/ s
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by2 a, ^! J  f0 k' i1 t* B9 R# m
skin slices of man. J. Clin. Invest., 48: 371, 1969.
2 o2 J- t/ K% o6 N5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. S+ ^. H* x2 B: T4 j( R3 f3 O9 \by topical application of androgens. J.A.M.A., 191: 521, 1965.$ r/ g7 T# r$ R( `. X0 q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% r/ S  J- }6 m" Z6 q4 y
androgenic effect of interstitial cell tumor of the testis. J.* P, @; X. |" v/ [& T4 B1 E2 d5 O
Urol., 104: 774, 1970.6 ^( o8 K6 f, K0 [% {- a
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
% G" P1 e* A6 }) d- Q# i+ C/ Q* w( _/ `tion in the male genitalia from birth to maturity. J. Urol., 48:
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