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Mohamed El Kholy , Rasha Tarif Hamza * , Mohamed Saleh and Heba Elsedfy" l, D# g" S+ J7 s' P# [. ]" s/ E) X
Penile length and genital anomalies in Egyptian
& e, R5 |4 T# e* h# lmale newborns: epidemiology and influence of0 A. @% i; T3 m
endocrine disruptors
  ?, Y, [2 t7 ^- |2 ]7 ]8 SAbstract: This is an attempt to establish the normal& o% R5 b- i- O/ q& l2 w
stretched penile length and prevalence of male geni-
2 h  k! T8 H: S# W1 `, n& @. ltal anomalies in full-term neonates and whether they
8 C: w2 A3 ]# K) jare influenced by prenatal parental exposure to endo-
  n8 V5 d# U8 k7 ocrine-disrupting chemicals. A thousand newborns were7 s  D/ v0 _# ]& ?; b
included; their mothers were subjected to the following
' c" J! J! b7 A: m8 j- b* T  t1 Iquestionnaire: parents ’ age, residence, occupation, con-
- G: ^+ X2 b  [6 S& P7 q, o; B1 Ytact with insecticides and pesticides, antenatal exposure
9 t1 _7 y. V3 n; [to cigarette smoke or drugs, family history of genital$ C" Y% T5 @# x3 G5 U5 m
anomalies, phytoestrogens intake and history of in vitro
* L. e6 c2 I! U+ [. a* \+ d' y- ofertilization or infertility. Free testosterone was measured* e4 ^/ u0 X8 J! k8 |
in 150 neonates in the first day of life. Mean penile length
! D5 N  v8 D' K: Awas 3.4 ± 0.37 cm. A penile length < 2.5 cm was considered0 P- Q2 h( r# }/ k& x2 j
micropenis. Prevalence of genital anomalies was 1.8 %+ F% D' c1 J) D1 s
(hypospadias 83.33 % ). There was a higher rate of anoma-4 H9 t5 d; H6 ~2 T: M) Z" R' V
lies in those exposed to endocrine disruptors (EDs; 7.4 % ); u/ Q  w% W# s4 F- t' \1 e
than in the non-exposed (1.2 % ; p < 0.0001; odds ratio 6,8 h) x. }7 e; q& q- C( Z
95 % confidence interval 2 – 16). Mean penile length showed
3 C: S6 [+ v. l0 i9 Ba linear relationship with free testosterone and was lower8 J6 o, l! j( k$ R' X
in neonates exposed to EDs.
: j/ ?; d) S4 \1 SKeywords: endocrine disruptors; genital anomalies; male;
* _/ ]5 b0 z- ^  p( x" m9 Mpenile length; testosterone.) @* Q* P  g. c0 B8 |" [
*Corresponding author : Rasha Tarif Hamza, MD, Faculty of) b7 g/ F9 b; @  y/ T& m
Medicine, Department of Pediatrics, Ain Shams University, 369 u& `) U. Q/ o  W+ k9 S) i
Hisham Labib Street, off Makram Ebeid Street, Nasr City, Cairo
+ ~: t# z* z; n7 j9 x" e0 G11371, Cairo, Egypt, Phone: + 20-2-22734727, Fax: + 20-2-26904430 ,
$ n$ ~. q# s+ G. w- {" S% d. ]/ L4 sE-mail: [email protected]
( r7 z# |- D. A/ bMohamed El Kholy, Mohamed Saleh and Heba Elsedfy: Faculty of
( }1 j& k& ]  v1 R0 h6 [9 h9 ]Medicine , Department of Pediatrics, Ain Shams University, Cairo,
% M3 s, w  O3 Q: }  E, I4 LEgypt% m2 T6 F8 @. Z
Introduction
7 x- N: I& h0 BDetermination of penile size is employed clinically in; [" e, L* f0 {4 H9 A
the evaluation of children with abnormal genital devel-0 S, K8 s& O6 [% B
opment, such as, for example, micropenis, defined as a
; e5 e% {$ C# h1 O  {penis that is normal in terms of shape and function, but is
9 M. v' [; u. u. o3 L1 Gmore than 2.5 standard deviations (SD) smaller than mean
; y2 y% ]6 U. R7 O; D# ksize in terms of length (1) . However, these measurements
# D+ [) \1 o1 T7 L: i7 kcan be subject to significant international variations, in' L! a8 ~" W. z/ @. W  T: p
addition to being obtained with different methodologies
! B) e  p8 x8 \$ J- e" `% o+ n! {in some cases (2) .
0 U7 A, Y! a; M0 z7 x0 cOver the past 20 years, the documented increase in: ]5 L! l$ U$ I1 b
disorders of male sexual differentiation, such as hypo-
( t* `7 S4 l' v" fspadias, cryptorchidism, and micropenis, has led to the
% Q5 j5 [( M' j' N) g# Tsuspicion that environmental chemicals are detrimental
0 k: g7 y8 Q# N2 ~to normal male genital development in utero (3) . The so-
$ i3 j' Q, \& Hcalled Sharpe-Skakkebaek hypothesis offered a possible
' w3 I, ]1 h: P  [common cause and toxicological mechanism for abnor-# S2 |# F& _. E5 e
malities in men and boys – that is, increased exposure to
8 u" F! o8 q1 @# ?. Foestrogen in utero may interfere with the multiplication( w2 U9 u, R% f- h6 H& V
of fetal Sertoli cells, resulting in hormonally mediated3 B% p, _  u. \1 G
developmental effects and, after puberty, reduced quality
; M; I7 f1 d7 M. L$ G1 iof semen (4) .
0 [  ^. \$ A! F+ p) F, mIt has been proposed that these disorders are part of
4 `# e) }8 g& B' b: \a single common underlying entity known as the testicu-
& e5 T/ O# L2 [/ K) z8 Jlar dysgenesis syndrome (TDS) (5) . TDS comprises various
$ S( e& }2 L8 p/ Yaspects of impaired gonadal development and function,
, P1 L4 B. Q7 Yincluding abnormal spermatogenesis, cryptorchidism,5 Y- `: o+ I1 c( j* N' |2 i
hypospadias, and testicular cancer (6) .4 J1 }4 P$ H' ]0 \, E$ `' J! Y! }
The etiological basis for this condition is complex
4 B8 h' x8 e0 x% land is thought to be due to a combination of both genetic
9 V; S* H9 g4 k6 d8 aand environmental factors that result in the disruption
  V0 l) S' ~6 ^: P3 _' G1 r8 c' cof normal gonadal development during fetal life. First,
! x/ H) g: @8 T/ X" zit was proposed that environmental chemicals with oes-# {& P& H5 c5 p/ |' \( p9 I' X, V0 R
trogen-like actions could have adverse effects on male5 {4 h. Z2 I6 ~- U! B' S* x
gonadal development. This has since been expanded to
* V& ^% L- \% d& t& b5 r. S- D1 Uinclude environmental chemicals with anti-androgen; ?, m" a/ j) v4 e6 X
actions and it is now thought that an imbalance between
( E/ |. j5 b( @androgen and oestrogen activity is the key mechanism by  r7 l- X- Q, g5 i
which exposure to endocrine disrupting chemicals (EDCs)
' _3 s* O4 K# {% Rresults in the development of TDS and male reproductive, v; f( `+ S( Y. ~, U9 |5 o
tract abnormalities (5) .' M/ g. C  B5 f8 Q
With the increasing use of environmental chemicals,6 ]7 n8 f5 |' ~6 \3 K
an attempt was made to establish the normal stretched
  u  r: M# y$ J; {. upenile length as well as the prevalence of male genital4 [$ y! @1 \* U, }
anomalies in full-term neonates and whether there is an( |. Z0 R8 L1 ~( |) r
influence of prenatal parental exposure to potential EDCs
6 j: o! F7 o+ o2 lon these parameters.: g7 K8 u" K/ a
Brought to you by | University of California - San Francisco/ w8 w$ c2 V* \; u8 P: ^( c
Authenticated
4 V" q  L+ W" X* N+ ]/ H$ aDownload Date | 2/18/15 4:26 AM
  H- @# Z* y6 r' {6 g510 El Kholy et al.: Penile length and male genital anomalies
+ C, S' p: a5 ZSubjects and methods
" n" @4 U. ]- D( ~- \Study population' F* C1 }2 Y* O
The study was conducted as a prospective cohort study at the Univer-
+ Z9 ?0 d3 C4 H2 Osity Hospital of Ain Shams University, Cairo, Egypt. A sample of 1000
! f. ?8 q2 e  v- ^male full-term newborns was studied.
7 n/ g% j9 I: }0 T% P3 L) xSampling technique( h3 Z' }# F3 o! `, v
Three days per week were selected randomly out of 7 days. In each
/ Y9 E$ g4 q) p1 r; `2 gday, all male full-term deliveries were selected during the time of fi eld  E3 H' z& S! t. i
study (12 h) during the period from March 2007 to November 2007.: j; P: q  f+ I/ P1 Q' v
Statistical analysis
$ Z: b3 e7 t9 j& R5 VThe computer program SPSS for Windows release 11.0 (SPSS Inc.,
" @7 W- e5 d' @1 m, Y: qChicago, IL, USA) was used for data entry and analysis. All numeric
/ \/ b7 N6 \; Zvariables were expressed as mean ± SD. Comparison of diff erent vari-
3 L2 h% }5 b: N& B& `ables between two groups was done using the Student ’ s t-test for$ H5 |2 S; O1 l8 y/ b% q/ m* ]
normally distributed variables. Comparisons of multiple groups were7 M# a5 P4 k2 m5 F" _
done using analysis of variance and post hoc tests for normally dis-
  A! Y# o) i' ^2 T* M2 ~/ Vtributed variables. The χ 2 -test was used to compare the frequency of
& r  Z6 K$ n8 q) _( N( Jqualitative variables among the diff erent groups; the Fisher exact test
4 `- F. T; @8 v: O, x& O1 M7 @* U: pwas performed in tables containing values < 5. The Pearson correla-
5 V+ A; [9 Y5 C. I4 O; w; U1 Ftion test was used for correlating various variables. For all tests, a
; w1 |5 ^5 C7 K* ~: A3 S9 P' s/ Sprobability (p) < 0.05 was considered signifi cant (10) ./ T$ u: E' w. B8 r8 j* ~
Results
+ C. |. n3 e; BData collected7 j+ T7 C9 D% `# J! ?& j6 T
A researcher completed a structured questionnaire during inter-$ d) |; I1 @2 h0 S4 |$ @8 q& i5 g
views with the mothers. The questionnaire gathered information
6 C9 x2 ~) m- {1 z( H; V& k# G. _% pon the following: age of parents; residence; occupation of the/ X  Y0 s1 N$ _& ~2 r
parents; contact with insecticides and pesticides and their type and
* {% f) T2 P0 T4 ?  ofrequency of contact; maternal exposure to cigarette smoke during
5 D% U# f$ H" @4 b) J/ D0 Apregnancy; maternal drug history during gestation; family history0 N' y8 U" v! o) H
of hypospadias, cryptorchidism, or other congenital anomalies; in-
1 q1 h9 f5 @- B) N' P4 etake of foods containing phytoestrogens, e.g., soy beans, olive oil,
' x: Z5 c6 I1 E( igarlic, hummus, sesame seed, and their frequency; and, also, his-# f/ I2 Q0 |  T
tory of in vitro fertilization or infertility (type of infertility and drugs
, m+ C0 C: A5 M& p& Ugiven).; |  f" e( }3 f$ o7 c: Q  |
Environmental exposure to chemicals was evaluated for its po-; v  ^. G- S" W! j! d2 U: B
tential of causing endocrine disruption. Chemicals were classifi ed
+ @2 O3 c+ x& E" q  Yinto two groups on the basis of scientifi c evidence for their having$ L5 a1 P: \* D$ z8 G/ m- T# k
endocrine-disrupting properties: group I: evidence of endocrine dis-
& }, Y: G  |$ [2 A( D+ _, R; Hruption high and medium exposure concern; group II: no evidence of' }+ B, w! y0 H2 |5 V
endocrine disruption and low exposure concern (7) .( X2 j  @/ Q# x5 |
Descriptive data. O) ]2 S9 K' S
The mean age of newborns ’ fathers was 36 ± 6 years (range! t6 x& h; U4 D: y3 J! Y1 f3 G
20 – 50 years) and that of mothers was 26 ± 5 years (range: a$ n5 [2 S. Z- f. F* G
19 – 42 years). Exposure to EDs started long before preg-/ b4 o& N. W' g
nancy and continued throughout pregnancy. Regard-
( e; \3 r, _3 g9 xing therapeutic history during pregnancy, 99 mothers* S( R1 F6 @3 ^, T" J
(9.9 % ) received progestins, 14 (1.4 % ) received insulin,2 v  w, o0 j% P) f0 P8 @
6 (0.6 % ) received heparin, 4 (0.04 % ) received long-9 Q" y: g9 m8 v- e. Y' a
acting penicillin, 3 (0.3 % ) received aspirin, 2 (0.2 % )% F8 n3 W5 p% p% }% `& e
received B2 agonist, and 1 (0.1 % ) received thyroxin,
" B# r6 }; [' A: O- Q0 `) y, @while the rest did not receive any medications during
. d" d  E" F' l# o* \pregnancy except for the known multivitamins and8 {+ v9 w7 s/ C. a4 H
calcium supplementations. In addition, family history7 j; ]! P+ Y3 E" o; ~8 U, R
of newborns born small for gestational age was positive
# P7 I8 A" S$ J9 ~0 ain 21 cases (2.1 % ).
3 ]9 i- P- s" B  R* pExamination
8 p2 x, [3 h% K& PIn addition to the full examination by the paediatric staff , each boy
, ]5 t6 n$ {6 hwas examined for anomalies of the external genitalia during the
9 [! e% Y. @+ zfi rst 24 h of life by one specially trained researcher. Examination% S5 e- n! R. s; m5 i  ]
of the genital system included measurement of stretched penile
4 y4 z/ T# T! p. ]8 R# tlength (8) and examination of external genitalia for congenital% m8 t. S- j, F" i" C, m2 S
anomalies such as cryptorchidism (9) and hypospadias. Hypospa-
3 y4 U9 F, N% S$ @& Q8 ], X4 h; h! qdias was graded as not glanular, coronal, penile, penoscrotal, scro-
% V5 H8 ~$ A0 P( u1 atal, or perineal according to the anatomical position. Cases of iso-
& u1 p% b4 E! e( x( x6 |; g! g0 k' Y# F. blated malformed foreskin without hypospadias were not included
9 E$ @* p8 K  H9 U1 H9 v9 ~as cases.% k9 a" z7 J  D. w) f+ f' V
Penile length# a" e4 {% E; N; ?, C/ a; U' t0 \
Laboratory investigations! Z; J" W' `, o# [: m
Free testosterone level was measured in 150 randomly chosen neo-' S& D. x5 o; k" f
nates from the studied sample in the fi rst day of life (enzyme im-
0 n; {0 m& {" U- N$ `% g* a3 tmunoassay test supplied by Diagnostics Biochem Canada, Inc.,( ~- j7 K3 q7 Z  B5 V  e
Dorchester, Ontario, Canada).
+ `4 ]9 X8 l( ]6 c+ I( w4 VMean penile length was 3.41 ± 0.37 cm (range 2.4 – 4.6 cm).5 ^7 x4 \: q9 K- `
A penile length < 2.5 cm was considered micropenis ( < the  s! [7 O* J# Z* ^- R! x
mean by 2.5 SD). Two cases (0.2 % ) were considered to
) J& |8 u- Q+ N$ {3 J+ Lhave micropenis. Mean penile length was lower (p = 0.041)
6 E1 Z8 n% m" p+ z4 ]in neonates exposed to EDs (n = 81, 3.1 cm) compared to the0 e8 B8 d( h6 [1 a
non-exposed group (n = 919, 3.4 cm; Figure 1 ).
2 Z  l& i7 ~4 u( c# l6 ^There was a linear relationship between penile length
. c: u1 y( N9 h6 [and the length of the newborn with a regression coef-
* l; Q2 _0 @% b" N# t+ }ficient of 0.05 (95 % CI 0.04 – 0.06; p < 0.0001), i.e., there
6 W2 }3 z- M9 ?) A0 k/ O% }! lwas an increase of 0.05 cm for each unit increase in length
# H4 d! y- U* f7 S' C8 w+ l(cm). Similarly, there was a linear relationship between: L, r  c& v# a. Z
penile length and the weight of the newborn with a regres-: }9 N" M$ x0 G+ X9 ?
sion coefficient of 0.14 (95 % CI 0.09 – 0.18; p < 0.0001), i.e.,7 F  Q9 ^/ `1 R& i) i6 q  o. S
there was an increase of 0.14 cm for each unit increase in
8 i. Q% x7 I6 u. a) Gweight (kg).
7 ^4 q2 l1 B7 \Brought to you by | University of California - San Francisco% w7 l& W  O  c* M
Authenticated% M! n* c- G+ l1 Y4 U
Download Date | 2/18/15 4:26 AM5 r' A1 h' D9 D+ ?5 V: w
El Kholy et al.: Penile length and male genital anomalies 511' r) u' l, }- M& L2 T" r# c6 K
3.45
* x8 g4 O2 z3 n9 @3.40
2 K. v6 c0 L2 p" j: L3.35
! G9 L6 |  m2 d5 \+ f3.30
+ U" z/ C2 R! X" [4 Y5 f$ N. ^3.25& M6 w+ x" i/ M5 @
3.20
2 D' D) b. y' w3.15" s6 g5 c& J' U  {  X5 _
3.10
7 w4 I  z2 g- }3.05
3 N6 P$ w2 f2 c3.00
6 h+ V# V. S6 a/ B3 t1 [; q3 g2.95# h$ U# @  t4 k
2.90
% ]3 F0 n8 ]8 nMean3 e" x9 j% L+ e, r7 A/ \- ~
penile
5 E& P! ^# t5 Tlength
3 E; \$ n1 F: w( D- `6 ^: p9 e7 Q. dan odds ratio of 6 (95 % CI 2 – 16), i.e., the exposed persons) h. G4 s9 \! b
were six times more likely to develop anomalies than9 v2 {. E/ K! g2 ?" T
those not exposed (Table 1 ).2 ^4 `& K' a, @3 d  F2 s1 M3 J
Genital anomalies were detected in the offspring: r! v  b$ x' K( D0 M. z% o7 r: d
of those exposed to chlorinated hydrocarbons (9.52 % ),' P. e9 _  C# u& n4 |: _3 B
phthalate esters (8.70 % ), and heavy metals (6.25 % ). In
+ P! L/ I0 S  z2 f) S0 ncontrast, none of the newborns exposed to phenols had
9 S; J7 n+ f6 E( ^genital anomalies (Table 2 ).' \0 R( Q7 I8 P! [. C' h+ Q
Exposed
  y# [9 g+ c. s; v7 T" ]9 R% WNon exposed/ r" l9 i  e) T& Y8 X) X: F
Penile lengths according to exposure to endocrine; o$ K$ [" w: p' x& L' K& Q! a
Figure 1 disruptors.
* J9 |# g  l' L% MSerum free testosterone levels) H# P# h. F* I0 ]" d  K  q
Exposure to cigarette smoke and progestins2 z* A( N  @) x+ l3 H7 q
during the first trimester& L% _0 ~3 r9 G( t6 Z
None of the mothers in the study was an active smoker;
% P8 j4 q, q; a350 were only exposed through passive smoking. There
  F4 G+ x0 u& u$ zwas no difference between rates of anomalies among* c8 o# H0 w6 L" N+ Q
those exposed to cigarette smoke when compared to those$ y# }+ Z4 s7 J
not exposed (1.1 % vs. 2.2 % ). Similarly, there was no differ-
1 @3 S, e1 z* h" tence between the rates of anomalies among those exposed0 V7 N! s5 B# [3 V  Q. m. @" H4 j
to progestins during the first trimester when compared to' ^: v- }4 S3 A4 R8 |
the non-exposed ones (2 % vs. 1.8 % ).
7 X5 ^5 k! s% C9 ~3 M8 H- {In the first day of life, serum free testosterone levels
7 g% H0 T9 _2 N0 T6 r: dranged between 7.2 and 151 pg/mL (mean 61.9 ± 38.4 pg/mL;
  e( u0 w6 ?  {! D6 z& H6 |median 60 pg/mL). There was a linear relationship
/ K3 x% l/ T/ c0 m+ c% Vbetween penile length and testosterone level of the
$ z% a% V, F9 F9 enewborn with a regression coefficient of 0.002 (95 % CI- p7 a% L: c6 d0 C: l5 K
0.0004 – 0.003; p = 0.01), i.e., there was an increase of 0.2 cm( H4 t/ a4 K* d3 ?. w1 G
in penile length per 100 pg/mL increase in testosterone" h( Q3 D* r9 @+ i% e# J
level. Moreover, serum testosterone level was significantly5 u9 e3 ]4 s0 V+ e4 V+ i6 P; P* ?7 {) T
lower in newborns exposed to EDs (49.50 ± 22.3 pg/mL)
; `8 k8 u& ~1 z9 p0 h# D& kthan in the non-exposed group (72.20 ± 31.20 pg/mL;# F" {. Y- |8 J. q0 B2 E2 A' k
p < 0.01)./ I' Z, @& s1 p6 `8 `
Table 1 Frequency of genital anomalies according to type of
/ ?$ ?# ~2 S* i7 P0 \1 mexposure to endocrine disruptors.
  L: M8 J2 Q# W/ |* G, b7 e, jExposure to endocrine/ G4 Q* c# d0 m. I
disruptors
- k& N% D: O, Q' I, QPrevalence of genital anomalies+ H: t: u! C1 T- C' H
Anomalies Total) q) Q7 T8 D" C0 s; O  Q$ y
Negative Positive4 w8 I! j7 L1 \+ w* u. y1 J; e; J6 O
Negative exposure 908 11 919" U* `+ i# R) Z9 @. v  A2 ?
98.8 % 1.2 % 100.0 %& H% B6 R1 }9 v1 N' ^% k$ W. P
Positive exposure 75 6 81
3 {  b$ d; j' `( d  X92.6 % 7.4 % 100.0 %
- f1 y, {, A% X9 \Total 983 17 1000
) j2 j7 D7 E5 H98.3 % 1.7 % 100.0 %3 W* m; _4 q% \% k) i  [* K" H
χ 2 = 25.05, p < 0.0001.3 R4 i3 J) w' o1 L# u: ~2 ]
Over the study period, the birth prevalence of genital
. d# `5 C# ?& n  V% r/ F+ ~+ Sanomalies was 1.8 % , i.e., 18/1000 live birth. Hypospadias- X. e6 t4 ?0 B3 l" V+ W8 @
accounted for 83.33 % of the cases. Fourteen had glanu-
( D  F% P  g! o+ N; J4 o* z4 Y  nlar hypospadias and one had coronal hypospadias. One
; i- c) x) U6 _+ h9 ]9 Mhad penile torsion and another had penile chordee. Right-
6 A) J) p+ @/ I. gsided cryptorchidism was present in one newborn.8 Y( o0 N) t' S' [* y# l
Exposure to EDCs
6 Z2 C% x1 x+ ]& yAmong the whole sample, 81 newborns (8.10 % ) were
- V6 U6 `' g( r, U2 Nexposed to EDs. The duration of exposure varied from% k% q- V: C/ U! D* k0 H  H, R: F
2 to 32 years with a frequency of exposure ranging from2 C! ?- J- g/ j; l
weekly to 2 – 3 months per year.
  J) t5 [& d- K+ \% |There was a significantly higher rate of anomalies7 ?& o) I/ X2 Q: R
among those who were exposed to EDs when compared
0 F! A$ r# ^( r/ [to non-exposed newborns (7.4 % vs. 1.2 % ; p < 0.0001), with
" J: w) [) F& @Table 2 Type of endocrine disruptor and percentage of anomalies in
9 m' ]" O5 A% Z& b) Ethe group of neonates exposed to endocrine disruptors (n = 81).
& J) Y  e; T- p; E) d5 w. [  E, t7 GAnomalies Total8 H. g8 q( b, B1 ~" H
Negative Positive3 L  K$ V4 @2 C: W) T/ d/ ~
Chlorinated hydrocarbons (farmers) 19 2 210 s  L2 T1 U/ z" k4 c
90.48 % 9.52 % 100.0 %
# p; G- m! u6 O; ~% G1 W5 T4 yHeavy metals (iron smiths, welders) 30 2 32
- I4 E9 Z4 @; w# t; H& s1 k93.75 % 6.25 % 100.0 %
4 M0 a( S# `5 ]# b, \% e3 V$ {Phthalate esters (house painters) 21 2 23
5 V* K0 |/ G( Y% W91.30 % 8.70 % 100.0 %
& }9 |1 @- Z& O* XPhenols (car mechanics) 5 0 5  N+ o4 K) w1 Z9 A' C) j
100.0 % 0 % 100.0 %6 p9 J$ ~- l, ~! {6 I( L! ?
Total 75 6 81
5 X2 f" z, n& A' ]  P& z& y/ E8 S92.60 % 7.40 % 100.0 %& R& f% L# c" j" V
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512 El Kholy et al.: Penile length and male genital anomalies
) J+ [0 O9 Q/ [+ |% R! VDiscussion
/ j' \% f( B3 B; `7 uPreviously reported penile lengths varied from 2.86 to 3.75 cm
" s( p" B, E& S* j8 a6 _(11 – 16) and depended on ethnicity. In Saudi Arabia (13) ," |7 |- |- K, C# J; L
mean newborn penile length was 3.55 ± 0.57 cm, slightly* {5 _$ f( e+ ?. h, }8 O) A
higher than our mean value. However, the cut-off lower
$ b5 ?5 t) q0 c' P: I6 flimit ( – 2.5 SD) was calculated to be 2.13 cm (vs. 2.5 cm in
6 [7 i3 |% }5 x' q, R3 a: Aour cohort). This emphasizes the importance of establish-
$ i9 @& I3 Q) aing the normal values for each country because the normal
. h9 ~  m+ b* c& qrange could vary markedly. In a multiethnic community,
+ Z; o7 O' p, w2 m# P) J' \a mean length of – 2.5 SD was used for the definition of
0 j1 D4 A3 W( t% B" U1 x+ Vmicropenis and was 2.6, 2.5, and 2.3 cm for Caucasian,
) O- \! @- q! |3 v! `East-Indian, and Chinese babies, respectively (p < 0.05).: E6 V9 s$ |/ ]3 f: ]
This is close to the widely accepted recommendation that
8 l4 l5 w; I, ^1 p! _% c1 y- ha penile length of 2.4 – 2.5 cm be considered as the lowest
) L& D1 p. Q7 K- Glimit for the definition of micropenis (8) . The recognition# o. N, f' E; P
of micropenis is important, because it might be the only4 V. v) z' K& |5 R8 f
obvious manifestation of pituitary or hypothalamic hor-
* M9 x9 s- l6 L6 S) wmonal deficiencies (17) .9 r6 a, G; f! L9 a5 c+ r  H# m
The timing for measurement of testosterone in new-
7 }0 b( ~- y* G0 Oborns is highly variable but, generally, during the first 2
+ e' B+ g3 c. B6 R2 kweeks of life (18) . In our study, serum testosterone level
" k1 }% A( P3 u: w9 Awas measured in all newborns on day 1 in order to fix a% v1 P. i* R4 r( u1 h0 H( ?
time for sample withdrawal in all newborns and, also, to
4 m6 ]) W1 Z; E6 nmake sure that all samples were withdrawn before mothers
) X; L8 s# F$ C6 awere discharged from the maternity hospital. We found a8 [6 _) ], h' D" l
linear relationship between penile length and testosterone3 F, Q5 B4 e& s& _+ O, y& [, h7 V
levels of newborns. Mean penile length was lower in neo-
" H1 \$ A4 }1 A, b, ]( ]" y: |' @1 l) knates exposed to EDs compared to the non-exposed group,
9 o& u( f% J5 N7 [1 B# p$ qwhich could be related to the lower testosterone levels in$ P+ I! r; {4 r. x
the exposed group. The etiology of testicular dysgenesis
1 R! k7 m% n4 H0 L9 n! P+ zsyndrome (TDS) is suspected to be related to genetic and/or
$ s" p$ R: @0 y9 W2 O; ^, Cenvironmental factors, including EDs. Few human studies
* F- x5 w2 O& H! o0 M4 q2 fhave found associations/correlations between EDs, includ-
# F) Q5 a2 W( \& ding phthalates, and the different TDS components (18) .
, a0 ~) K# \" A6 rSome reports have suggested an increase in hypo-
0 }9 h) p- y- v! f8 b* y5 cspadias rates during the period 1960 – 1990 in European& G  m0 v& Y/ k7 n. n
and US registries (19 – 23) . There are large geographical
  `1 q' G$ G. X: vdifferences in reported hypospadias rates, ranging from
  ^/ Z5 ~7 [1 b1 m0 V. r7 x2.0 to 39.7/10,000 live births (23 – 25) . Several explanations5 t/ C0 u% V( h! U/ w; K' G: b+ `8 s
have been proposed for the increasing trends and geo-
: c4 X0 ^' N- F* m1 Ugraphical differences. As male sexual differentiation is
( r/ V2 B, M+ \% Lcritically dependent on normal androgen concentrations,4 G" U4 O! l# k5 u/ l
increased exposure to environmental factors affecting
2 I1 J# x( \7 `4 [) d9 t! A$ uandrogen homeostasis during fetal life (e.g., EDs with
9 A) h! B9 n- p4 {estrogenic or anti-androgenic properties) may cause9 ]7 y7 [; k+ S: r" x" W* e% N
hypospadias (3, 4) .
) M3 g% L6 ?: e! @9 M- u" S8 U8 d$ ]In Western Australia, the average prevalence of hypo-
: {+ m! J$ P* e7 k6 H$ j. ]6 {spadias in male infants was 67.7 per 10,000 male births.8 Z8 }* n- `. r; |) x7 M0 d
When applying the EUROCAT definition (24), the average0 p+ w( T/ M# q& b$ M2 N3 v, |7 o
prevalence of hypospadias during 1980 – 2000 was 21.8 per
3 f( Z) x3 @% c6 q+ e3 x10,000 births and the average annual prevalence increased
2 O' Y: U3 A) F- a6 J$ d( Tsignificantly over the study period by 2.2 % per year. The  g0 S: A- ~4 T: [' ?! y' j; c% X. E
prevalence of hypospadias in this study was much higher
$ x$ ^/ e% t& D& @- Lat 150 per 10,000; by excluding glanular hypospadias, the6 I" o. b0 _6 L4 a& o+ h2 X
prevalence fell sharply to 10 per 10,000 (26) .8 E3 U8 w4 }8 E; P
We found a higher rate of anomalies among newborns8 Y2 D2 S3 m9 P- ?/ l% [
exposed to EDs when compared to non-exposed newborns+ ^3 Z5 p" _0 X3 w* p, k$ b$ h
(7.4 % vs. 1.2 % ); this raises the issue that environmental
2 f) u: U1 R4 e% h% ?pollution might play a role in causing these anomalies.  M' C$ s' _1 o% p# m% v
Within the last decade, several epidemiologic studies4 y0 O% T  [5 s& q: _8 E6 y0 N1 n0 x
have suggested environmental factors as a possible cause
" C, b* {% W: K) [' u5 gfor the observed increased incidence of abnormalities in
. L" S" K6 |  @* C4 jmale reproductive health (27) . Parental environmental/- x7 ~2 V3 f$ r% K6 g
occupational exposure to EDs before/during pregnancy
" r+ ?0 U1 a& _2 q# Aindicates that fetal contamination may be a risk factor for
6 U) g$ j5 X3 wthe development of male external genital malformation
3 k/ m% u# M) J+ k' ](27 – 29) .  X; h& {8 x: x4 V9 a$ Y
Received October 25, 2012; accepted January 27, 2013; previously+ k: H1 F0 z' O; ~1 R
published online March 18, 2013$ v+ j( _! D2 K
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according to ethnicity ? Horm Res 2001;55:278 – 81.& x$ M, W  \2 a" N% R! S9 e: ^, F
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# q3 k1 K0 L! G( Q9 U% w# A21. K ä ll é n B, Bertollini R, Castilla E, Czeizel A, Knudsen LB, et al.
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- g* W6 E  O. t! M4 K# h22. Paulozzi LJ, Erickson JD, Jackson RJ. Hypospadias trends in two; g6 ^3 K* K2 \! A' |% ^+ p
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$ g# t# L& {4 x- Q3 G& p1 r9. Scorer CG. The incidence of incomplete descent of the testicle at
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; T  ?& [0 b, |. Z  k5 ppenile size in the newborn infants. J Pediatr 1975;87:663 – 4.
+ {1 z$ |/ `. x& @/ Y12. Ozbey H, Temiz A, Salman T. A simple method for measuring7 A+ r* h( T: H6 E: i
13. Al-Herbish AS. Standard penile size for normal full term3 ^  @& T% h4 d5 N5 W- ]% @, C2 E) z
newborns in the Saudi population. Saudi Med J 2002;23:314 – 6.7 q* w% c% j5 `
14. Lian WB, Lee WR, Ho LY. Penile length of newborns in Singapore., u8 q4 P2 N( ?: L
15. Pediatr 1995;62:593 – 6.9 f, l- X. _6 ~6 o7 }
16. Boas M, Boisen KA, Virtanen HE, Kaleva M, Suomi AM, et al.
$ Q! ?* x% }/ t- rPostnatal penile length and growth rate correlate to serum( R# f7 o7 a0 J
testosterone levels: a longitudinal study of 1962 normal boys.
+ d- g, u6 L  u' q" iEur J Endocrinol 2006;154:125 – 9.
# w+ ~# k5 I" z17. Camurdan AD, Oz MO, Ilhan MN, Camurdan OM, Sahin F,5 f3 K! U! U6 q0 V% Y) |+ F
et al. Current stretched penile length: cross-sectional study
% @; O4 J5 t% pof 1040 healthy Turkish children aged 0 to 5 years. Urology
6 \" o+ [+ ^' h2007;70:572 – 5." V4 A; x4 W3 t
18. Bay K, Asklund C, Skakkebaek NE, Andersson AM. Testicular
6 w' S- d7 |9 t/ A; k+ Vdysgenesis syndrome: possible role of endocrine disruptors.! L/ e. w; a  h/ d$ D# {
Best Pract Res Clin Endocrinol Metab 2006;20:77 – 90.( Y9 `" V9 [- g% p
19. Czeizel A. Increasing trends in congenital malformations of male1 n$ d, p7 K% \6 a  X
external genitalia. Lancet 1985;i:462 – 3.
  x6 z2 O9 F: L20. Matlai P, Beral V. Trends in congenital malformations of external
; b0 W' v) i; d1 Zgenitalia. Lancet 1985;i:108.
; s/ P, b4 U* `$ Y. E3 d4 Z23. Paulozzi LJ. International trends in rates of hypospadias
! l2 S# o! a2 T6 q6 m+ y8 Cand cryptorchidism. Environ Health Perspect 1999;107:
2 ~9 J7 x% V2 T7 D8 l& f5 s, K7 d# m297 – 302.) P' B0 @/ ~: n# z# z
24. EUROCAT Working Group. EUROCAT report 7. 15 years of+ z/ n$ O( @. `2 I+ M2 D7 P/ U/ E7 @
surveillance of congenital anomalies in Europe 1980 – 1994.
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; ~' G. m9 x7 f* I' y0 T: g) @  U7 VPasteur, 1997.
9 Q# t6 [; n. g8 A6 R6 Y* G( m25. Toppari J, Kaleva M, Virtanen HE. Trends in the incidence  o* @! F# f& O- ~$ o
of cryptorchidism and hypospadias, and methodological
2 h" Q1 B2 C: |/ R0 Alimitations of registry-based data. Hum Reprod Update4 \, y4 d+ P; Z
2001;7:282 – 6.
$ H9 [* v0 j0 `  U/ Z. j# T$ u26. Nassar N, Bower C, Barker A. Increasing prevalence of
. s2 {: L( {/ ^7 `6 h; S+ Yhypospadias in Western Australia, 1980 – 2000. Arch Dis Child
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+ h: ?) R" }" Q. B: D! H8 N. `6 k27. Wang MH, Baskin LS. Endocrine disruptors, genital
9 _- `1 O' u' N# z, q& vdevelopment, and hypospadias. J Androl 2008;29:499 – 505.
2 Y) E3 s5 s$ E28. Morales-Su á rez-Varela MM, Toft GV, Jensen MS, Ramlau-Hansen8 x! N( m2 l& J8 C, o
C, Linda Kaerlev L, et al. Parental occupational exposure to1 \; ]( r2 h3 b3 a- y$ f
endocrine disrupting chemicals and male genital malfor-6 ?: @0 U7 {% z* N$ g
mations: a study in the Danish National Birth Cohort Study.
' h' ]2 ^* I$ M# ^Environ Health 2011;10:3.
. U& h, J" ~. n. ?+ B# N$ U3 c% l29. Gaspari L, Sampaio DR, Paris F, Audran F, Orsini M, et al. High3 x  _& Z1 f% B) O* M
prevalence of micropenis in 2710 male newborns from an
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- l! ^- y- Z  @0 x# lGONADOTROPIN
9 e2 t1 J8 ?4 P/ q2 uRICHARD C. KLUGO* AND JOSEPH C. CERNY2 N3 X/ O  \! j
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% {- _3 M; u7 ], d6 s' y
ABSTRACT* O" B! ~% `: M/ y* e* [0 z
Five patients were treated with gonadotropin and topical testosterone for micropenis associated5 `  W  `5 p! x, y8 ]8 I
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
1 @; [5 R: |" Q# Utropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' T+ L/ w8 ^* i3 Y) o: F
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
, K+ l' D' ?" o, B# d- d. @0 }- Ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ o  R0 _( v, n* l7 f. U0 wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ e6 {3 I+ }$ h5 I8 y$ u: r
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 _1 r/ v: @, ^( ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 o5 l6 w' [. L* C3 W% V
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile( g- s$ t: J% e# S& h, Z& x& I
growth. The response appears to be greater in younger children, which is consistent with previ-- }6 B5 f; l& G
ously published studies of age-related 5 reductase activity.# O) N, h0 s0 w
Children with microphallus regardless of its etiology will
$ d: c- b' U. Lrequire augmentation or consideration for alteration of exter-2 a+ I. B4 `3 Z. r, Z0 d
nal genitalia. In many instances urethroplasty for hypo-8 H0 L. ?% Y8 U& m5 {; [# L8 k
spadias is easier with previous stimulation of phallic growth.
& }! T. r# \; C- k" XThe use of testosterone administered parenterally or topically
+ K& a& h+ S! G- _% `1 @# ~; Ehas produced effective phallic growth. 1- 3 The mechanism of
* s: I7 R+ z! Mresponse has been considered as local or systemic. With this1 b9 }: |) U3 S. ], B6 W
in mind we studied 5 children with microphallus for response
3 E" o5 j0 P! e9 Q) `4 @1 y/ ~( Oto gonadotropin and to topical testosterone independently.
! m' e8 |1 J& V2 c9 [MATERIALS AND METHODS
, n8 R% P* u# r$ K+ b3 W2 mFive 46 XY male subjects between 3 and 17 years old were
4 n8 m3 ]0 Y& ?5 }6 w0 uevaluated for serum testosterone levels and hypothalamic+ J7 ^6 D% r" {0 [! e6 z
function. Of these 5 boys 2 were considered to have Kallmann's; M+ e* T5 r) z; A7 S3 ]/ f
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
* }6 }, B) L: i! w/ ~! Blamic deficiency. After evaluation of response to luteinizing
+ J5 u' l/ B& Khormone-releasing hormone these patients were treated with! l2 s$ _) B+ l6 C; r
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) ^3 B' Q9 `9 a- l7 o8 }after completion of gonadotropin therapy 10 per cent topical$ D/ Q, {2 V3 a$ c) ^
testosterone was applied to the phallus twice daily for 3 weeks.
, u! Z$ n: d) ?5 b5 u. k: q3 _) ]Serum testosterone, luteinizing hormone and follicle-stimulat-
* _0 W, ?: @" ]3 g4 y6 D: t, aing hormone were monitored before, during and after comple-
! o0 h0 N3 h- A  W4 v; P; Dtion of each phase of therapy. Penile stretch length was
3 V3 m' ?3 b( u  [9 Z9 K' Robtained by measuring from the symphysis pubis to the tip of2 K# x$ Y# K. T. i
the glans. Penile circumferential (girth) measurements were, ]  `* _' z. @9 p7 S
obtained using an orthopedic digital measuring device (see. a$ T* W: c9 q9 r! a  ?' N$ H
figure).
& n% G; i" D, z9 ^& `RESULTS
# G7 u  A: Z1 W# }; HSerum testosterone increased moderately to levels between
0 ]4 k& P/ ]* S1 P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) e) e. C5 {8 tterone levels with topical testosterone remained near pre-3 U# W4 ?7 M, p' M# o$ j* g0 n; c
treatment levels (35 ng./dl.) or were elevated to similar levels
6 ~* q3 `& W  t8 V7 s, M* K% Mdeveloped after gonadotropin therapy (96 ng./dl.). Higher% Y4 k! T+ Q5 |% P
serum levels were noted in older patients (12 and 17 years old),
  u9 S3 N/ m+ l) Ywhile lower levels persisted in younger patients (4, 8, and 109 a7 H# y4 y7 p" I# o) x1 R
years old) (see table). Despite absence of profound alterations
' c0 x7 ]) @7 h( @- ]0 g" t( }of serum testosterone the topical therapy provided a greater5 q, ^6 j4 Y5 e/ C( A
Accepted for publication July 1, 1977. ·/ M2 W! j) ^2 E6 v" ]0 O% d6 P
Read at annual meeting of American Urological Association,
* j' d! F0 B7 K$ o* K6 P$ JChicago, Illinois, April 24-28, 1977.8 w, f% Y8 `7 }" ~
* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 S# {' ?" N) f2799 W. Grand Blvd., Detroit, Michigan 48202.
- g: {& Z& Z( N) Rimprovement in phallic growth compared to gonadotropin.
2 o2 a. W7 F) _0 l  b/ _Average phallic growth with gonadotropin was 14.3 per cent( M; v& _3 Y. w7 P) [5 u
increase in length and 5.0 per cent increase of girth. Topical1 m/ F  ^% N. [4 ~' Z
testosterone produced a 60.0 per cent increase of phallic length
4 l6 v; @* M" U8 Yand 52.9 per cent increase of girth (circumference). The7 J9 P: A9 z- j
response to topical testosterone was greatest in children be-7 ^  }( X, v% q. F1 {& k- z9 f
tween 4 and 8 years old, with a gradual decrease to age 17% o7 E8 I/ K" C8 J* w1 l
years (see table).
* w1 I- Q4 {+ y3 V: t! {5 D% }DISCUSSION
" G0 x" M2 _- m8 STopical testosterone has been used effectively by other% Q8 o6 [( u1 Z; v
clinicians but its mode of action remains controversial. Im-6 W5 c, K- Z2 X6 }
mergut and associates reported an excellent growth response
; B3 \8 u  K  R6 C* [( g4 r5 xto topical testosterone with low levels of serum testosterone,. h3 [2 c* j2 S
suggesting a local effect.1 Others have obtained growth re-4 O" p" C% c1 K7 w: P
sponse with high. levels of serum testosterone after topical5 P4 y' z0 Z' _: `
administration, suggesting a systemic response. 3 The use of
" I( h+ u7 p$ c# t! y3 Dgonadotropin to obtain levels of serum testosterone compara-8 I, j0 m, K- ~( v% P" }
ble to levels obtained with topical testosterone would seem to
' s- I7 T$ }) {6 Eprovide a means to compare the relative effectiveness of
7 N/ P+ p/ @( K5 ltopical testosterone to systemic testosterone effect. It cer-3 v/ X4 J" v8 l" v: J
tainly has been established that gonadotropin as well as par-( R$ n% {2 P7 j+ N" T4 O3 k
enteral testosterone administration will produce genital
- T. F( A  O' b8 o0 w2 D4 tgrowth. Our report shows that the growth of the phallus was
( j1 I/ O: v7 _significantly greater with topical applications than with go-
0 w) W2 _& m. K9 G; gnadotropin, particularly in children less than 10 years old.
4 t: T" P, P7 t2 C4 H4 @& Q: e( JThe levels of serum testosterone remained similar or lower& M. K5 _! A" i4 @) `. }- ^
than with gonadotropin during therapy, suggesting that topi-/ e) z: `; W9 A8 J- i6 }/ T/ r
cal application produces genital growth by its local effect as
( k( _9 I2 p' K' m" S7 x1 qwell as its systemic effect.' q( ]% ]4 }! U+ i/ C
Review of our patients and their growth response related to% {# J. N# |8 b- l
age shows a greater growth response at an earlier age. This is
+ d* u9 d3 k. U9 Fconsistent with the findings of Wilson and Walker, who/ c; R; C, ~3 F$ E& Q- m9 y2 S
reported an increased conversion of testosterone to dihydrotes-
! N2 Q' L- D6 J, P* Ztosterone in the foreskin of neonates and infants.4 This activ-# o% P3 I7 y! S9 k7 B- s
ity gradually decreases with age until puberty when it ap-7 Z( |1 Q' \0 u  a/ s
proaches the same level of activity as peripheral skin. It may
  {% K  J' K: Z6 A7 swell be that absorption of testosterone is less when applied at1 i1 J0 A9 |0 ~0 j2 i) ?# }
an earlier age as suggested by lower serum levels in children3 ^( f( A! l( _' W7 [* {7 h! r
less than 10 years old. This fact may be explained by the0 @5 ^# ~' x) B6 r# f" t( Q9 m* N! f
greater ability of phallic skin to convert testosterone to dihy-$ @3 J, l9 K* t, ?/ N- R- g# i
drotestosterone at this age. Conversely, serum levels in older
% \+ {& E4 h' _' v5 Y+ K" R  Kpatients were higher, possibly because of decreased local6 g, B* r( S( B1 W2 U/ z- ~6 l
667
8 o9 V! j. j, H3 I0 i668 KLUGO AND CERNY
* V- ^2 u7 \% r! ~Pt. Age  Z) Z( M( H6 E7 c* B4 g' T9 G6 b5 @" X
(yrs.)
+ m; D1 \" N- c4 [Serum Testosterone Phallus (cm.) Change Length7 h. G0 h- {5 k
(ng./dl.) Girth x Length (%)& n* w) G7 a/ ?8 u( G- h. b
49 y  X: S# T( @7 E$ b
8* Y- V8 m4 R7 u3 C. M
10& v1 W9 T: v1 v* X# p% n8 K& f
12
% M6 C* D; k; m8 X& Z) U) }8 ~$ i' H17
) M0 b$ q7 R0 R& s+ tGonadotropin; W% N; o& D8 Y0 G! Q8 @
71.6 2.0 X 3 16.6/ C' C& j8 B4 I( Q
50.4 4.0 X 5.0 20.0
# H* `/ I5 I; i  m) m22.0 4.5 X 4.0 25.0! d! ?- u$ t" \& j
84.6 4.0 X 4.5 11.1
3 o. i3 e) |1 r! V6 ]& k85.9 4.5 X 5.5 9.0
- `3 f: V0 Y7 Z+ |! f) HAv. 14.3
' H' n- k- A% r$ _- u4, `' w  {  k3 \: x& y
8" n, ?4 \' \2 `2 J: w% ~
10
" ~2 x1 g# `( y! T125 E9 A( e3 m3 H
176 H6 l$ _- \0 v
Topical testosterone4 {2 Q+ N  A+ h' L
34.6 4.5 X 6.5 85" K. e* H7 m" q! F/ i- r3 n8 |
38.8 6.0 X 8.5 70
; [- k( w# J) r( P+ s40.0 6.0 X 6.5 62.5& |7 o1 n* i; D' h4 u1 `# h
93.6 6.0 X 7.0 55.5
; U) C, [, }* Y6 ~; g- o0 F# i: v+ g95.0 6.5 X 7.0 27.2
3 u& F; z1 g/ @5 ~, x( s# `Av. 60.09 ?4 T" _4 p, y# [, l
available testosterone. Again, emphasis should be placed on
: l* I3 o' W  J2 S1 n' j+ Nearly therapy when lower levels of testosterone appear to. u* ~( I6 S' p1 F; a( @& w/ {' V
provide the best responses. The earlier therapy is instituted4 o: T7 I  B* l. X
the more likely there will be an excellent response with low
6 ^" y1 y+ p) k; _serum levels. Response occurs throughout adolescence as1 t/ ]# R5 w( g% m, i
noted in nomograms of phallic growth. 7 The actual response; _4 b$ `$ A/ c6 m
to a given serum level of testosterone is much greater at birth
, f1 b& }" Q4 c% G" R$ [5 b+ pand gradually decreases as boys reach puberty. This is most
/ i' A3 }( U- M7 a+ E) m6 ilikely related to the conversion of testosterone to dihydrotes-  j( Q0 v! b1 [4 F$ W
tosterone and correlates well with the studies of testosterone8 q: r9 S0 ?6 V- g8 ^& x1 V
conversion in foreskin at various ages.2 C5 T/ E& ~& q8 q% @( [
The question arises regarding early treatment as to whether
8 Y: ^8 q0 p! R' Fone might sacrifice ultimate potential growth as with acceler-
1 P: y- x  @/ M, u( Jated bone growth. The situation appears quite the reverse
+ Q# F3 w* V" u: ^0 \; w! P- |with phallic response. If the early growth period is not used
% r/ s1 O, @$ V+ s$ `! Swhen 5a reductase activity is greatest then potential growth3 X3 z7 _. X. d: k1 L' f: L2 X7 X! A
may be lost. We have not observed any regression of growth4 g# K# K. Z/ H) j6 ~
attained with topical or gonadotropin therapy. It may well: Y" e0 W. H# C2 `$ _5 t0 s( X
be that some patients will show little or no response to any
% ^# Z, O5 v/ T# F) a- s7 sform of therapy. This would suggest a defect in the ability to7 Q' J# i1 g. f$ _- u
convert testosterone to dihydrotestosterone and indicate that' c% u+ o  Y. v% S# g/ w" d. |3 ]$ f
phallic and peripheral skin, and subcutaneous tissue should
8 ^# F+ h$ `- h: Nbe compared for 5a reductase activity.# {3 p% s; V) V$ I4 d
A, loop enlarges to measure penile girth in millimeters. B,& r/ C4 e, @) E
example of penile girth computed easily and accurately.
& l& t  B5 b. Nconversion of testosterone to dihydrotestosterone. It is in this
' X* I5 Z* G/ x: k' kolder group that others have noted high levels of serum
% }4 N8 R: q& K  Ptestosterone with topical application. It would also appear
9 e( V+ ]9 k& B4 n( nthat phallic response during puberty is related directly to the
4 T; X( ~' W6 k; Vserum testosterone level. There also is other evidence of local1 [1 ?) I0 \" X; \5 ]% K
response to testosterone with hair growth and with spermato-
7 W5 ^1 Z+ l, Jgenesis. 5• 65 Y; H( H% e% ~, }% S
Administration of larger doses of gonadotropin or systemic: L7 `9 J# {1 K" G
testosterone, as well as topical applications that produce4 V! }; ?; C( \& y5 O/ @
higher levels of serum testosterone (150 to 900 ng./dl.), will( ~" V) Q3 a' t" r8 a0 x* i
also produce phallic growth but risks accelerated skeletal* ^( \% }' h" m: c; F3 T# X$ F2 q
maturation even after stopping treatment. It would appear) }4 d  o! z2 r
that this may be avoided by topical applications of testosterone' E' ^6 u. @" Q# x* F5 B
and monitoring of serum testosterone. Even with this control
3 ]& Y1 d0 O7 w, Z# othe duration of our therapy did not exceed 3 weeks at any9 [# v3 m$ \  q- O) ]0 H
time. It is apparent that the prepuberal male subject may+ N' e7 @: s1 I9 X7 o) \
suffer accelerated bone growth with testosterone levels near
2 ?/ w! r) j- \/ r. \7 c7 R& }200 ng./dl. When skeletal maturation is complete the level of  S! e; r( B( c2 [: ~# S
serum testosterone can be maintained in the 700 to 1,300 ng./0 E% t: a7 F! _- r
dl. range to stimulate phallic growth and secondary sexual! T7 e: w2 f' Y  `3 A( \
changes. Therefore, after skeletal maturation parenteral tes-5 Q3 }/ K. P* @  `
tosterone may be used to advantage. Before skeletal matura-) _% ~/ J7 r3 K3 `+ R- I
tion care must be taken to avoid maintaining levels of serum
+ q. z* _; R: ?; e' a( z2 w+ r- dtestosterone more than 100 ng./dl. Low-dose gonadotropin6 z; Y( Q9 Y2 r. {$ m' Q/ |
depends upon intrinsic testicular activity and may require* }3 G5 u+ O! t
prolonged administration for any response.
  u' G9 L, V- P0 a; R/ Y9 a& K! V8 IAlternately, topical testosterone does not depend upon tes-
9 e& S  ~/ J: u  c  y! N) W. @ticular function and may provide a more constant level of
; o0 L7 B+ S  a& H2 J# }- l: MREFERENCES
3 T. Q$ R" V9 @! o# d1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! R5 r( n+ o  T# J! N
R.: The local application of testosterone cream to the prepub-3 _' p' i: X# J- d& q
ertal phallus. J. Urol., 105: 905, 1971.' {' p& ]0 i& a- I
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone! w0 }$ U1 J- `- d5 s7 \
treatment for micropenis during early childhood. J. Pediat.,
& u" _. D. p2 ?' s6 t) I83: 247, 1973.; k% _; U- d+ X( }6 B! G, ~; r, R
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' x% x! H* k6 [  a3 `) _one therapy for penile growth. Urology, 6: 708, 1975.' I& G9 e3 ?2 p2 D7 ]; a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 M9 _- g3 ^6 F9 H  G- B9 H" c6 L: S
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by- B) v" X1 k- x- ?9 o" @. T& }
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 }& t1 r0 C: ~, Y9 T& e% y/ h7 B5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. @) J& B( m. z' g' t8 h- M4 Rby topical application of androgens. J.A.M.A., 191: 521, 1965.) f/ b1 V5 a+ U% @
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local( }; @3 D6 m: b" W6 A' E0 v. S
androgenic effect of interstitial cell tumor of the testis. J.
$ e5 @: L  X4 i! ^+ O+ d/ A/ ~Urol., 104: 774, 1970.6 j  q0 J1 {% c. H1 r: y. K9 W
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" Y( ^7 {- L% G! f2 d5 n/ G
tion in the male genitalia from birth to maturity. J. Urol., 48:
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