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Mohamed El Kholy , Rasha Tarif Hamza * , Mohamed Saleh and Heba Elsedfy
. y4 \5 c& N4 f- HPenile length and genital anomalies in Egyptian$ }7 {9 C$ M" f! X& S6 Y
male newborns: epidemiology and influence of
# a/ O3 `9 x% O: Bendocrine disruptors
/ `6 K  e' |6 @2 ^Abstract: This is an attempt to establish the normal' W9 J6 I, K: n6 q
stretched penile length and prevalence of male geni-6 k. N( N5 m0 @1 F4 R, I; o( P
tal anomalies in full-term neonates and whether they9 @* t  v+ ]- c: v: K" |
are influenced by prenatal parental exposure to endo-# `$ ~' O! ]4 p% j- S0 ^5 N4 `
crine-disrupting chemicals. A thousand newborns were& a" X0 _4 N5 j+ {3 E# H& P9 U9 w
included; their mothers were subjected to the following1 {- {# p0 @& X& f; Y  ?
questionnaire: parents ’ age, residence, occupation, con-
0 M; f- M. U0 q: htact with insecticides and pesticides, antenatal exposure- @& f3 a3 F* c4 i
to cigarette smoke or drugs, family history of genital
# D* @* @9 a( Lanomalies, phytoestrogens intake and history of in vitro
0 ~  o% y) A7 Z+ F1 ^# O0 i* Hfertilization or infertility. Free testosterone was measured3 N. ^% ~8 n4 J0 G( W) i
in 150 neonates in the first day of life. Mean penile length
0 C7 U4 J" m' L1 k( R& ]0 ]was 3.4 ± 0.37 cm. A penile length < 2.5 cm was considered
3 ^9 V' {% R4 Mmicropenis. Prevalence of genital anomalies was 1.8 %& e' j, L* i1 O  I, \
(hypospadias 83.33 % ). There was a higher rate of anoma-9 w: N- O! v/ n9 B3 ~
lies in those exposed to endocrine disruptors (EDs; 7.4 % )  `, Z( r/ \, r4 J" w
than in the non-exposed (1.2 % ; p < 0.0001; odds ratio 6,. l0 f( s+ H& G' l- T* N) m6 R$ t' f
95 % confidence interval 2 – 16). Mean penile length showed+ }! i, T* a2 w8 I
a linear relationship with free testosterone and was lower% i# Q8 ]- l+ k/ r, y2 C; ]
in neonates exposed to EDs.
7 S6 o: L4 F! O  F& J! g3 z, TKeywords: endocrine disruptors; genital anomalies; male;
" ?$ i, f3 k5 @8 m) Mpenile length; testosterone.
* o8 W) H. b- c: P& H* C+ L*Corresponding author : Rasha Tarif Hamza, MD, Faculty of6 s0 J2 p" w' b+ `# e: \: m5 H8 J4 [
Medicine, Department of Pediatrics, Ain Shams University, 36! n! v8 o, F1 Y3 X8 Q+ b- x
Hisham Labib Street, off Makram Ebeid Street, Nasr City, Cairo3 r  D; y" i% _8 q' ^
11371, Cairo, Egypt, Phone: + 20-2-22734727, Fax: + 20-2-26904430 ,
" ~# z! g" R0 Q9 n2 _  {E-mail: [email protected]2 h/ ~$ C) i& b3 H) V% h
Mohamed El Kholy, Mohamed Saleh and Heba Elsedfy: Faculty of5 @' w7 T. v# p2 F/ H" ?
Medicine , Department of Pediatrics, Ain Shams University, Cairo,3 r- C2 H' ~* S( k6 Q. E. \$ o
Egypt
+ w8 v& H' E7 V- M+ [0 A7 W% ^! t- MIntroduction# t% Y1 x- ?1 _- Z/ j. w: B8 C3 U
Determination of penile size is employed clinically in" F  k2 F, {( B& x' a
the evaluation of children with abnormal genital devel-! r$ ]' G" a/ ~0 E
opment, such as, for example, micropenis, defined as a
4 H% T2 ?: {6 W; u+ Fpenis that is normal in terms of shape and function, but is
- f! a# I6 D) E( k' x3 l, ^more than 2.5 standard deviations (SD) smaller than mean" K; `1 c1 ?. l- N) k
size in terms of length (1) . However, these measurements
' [" v5 ~- q% r4 {; Zcan be subject to significant international variations, in, P; D! w  ~  g
addition to being obtained with different methodologies
% q5 [" k2 P  f0 V$ C* z1 J, }. _in some cases (2) .
7 ^- D6 H/ q# x3 FOver the past 20 years, the documented increase in! v( B' R$ g+ _  F& L7 O
disorders of male sexual differentiation, such as hypo-  ]: D% o# o  M" S# a7 C
spadias, cryptorchidism, and micropenis, has led to the
4 H2 Q# }6 v) r/ O% Z- Lsuspicion that environmental chemicals are detrimental
, \* y4 U9 ?2 k1 V9 G7 _to normal male genital development in utero (3) . The so-; U) r1 z- b6 i* {' w
called Sharpe-Skakkebaek hypothesis offered a possible& J$ c. g2 m6 Z- D
common cause and toxicological mechanism for abnor-- k7 B" z- W& X
malities in men and boys – that is, increased exposure to
% u2 N2 S$ X  a: _' Zoestrogen in utero may interfere with the multiplication
& x' t$ \- k! o- s0 n, p2 z6 Iof fetal Sertoli cells, resulting in hormonally mediated
- E& o+ j  f1 D3 d) M; t+ Rdevelopmental effects and, after puberty, reduced quality; Q/ h) _. Y7 n& |+ [
of semen (4) .
; T: s9 Z, M, D) ?: j. D/ \It has been proposed that these disorders are part of
2 e: L3 i! F% {  ya single common underlying entity known as the testicu-$ K3 O) F7 q1 M* C+ o& G
lar dysgenesis syndrome (TDS) (5) . TDS comprises various, `6 p0 g* M$ {+ k" F( G9 ~
aspects of impaired gonadal development and function,
8 h( d  U6 b0 l" F' O" }. Mincluding abnormal spermatogenesis, cryptorchidism,
. |9 P4 I; K6 E; W, p, rhypospadias, and testicular cancer (6) .
, X  v( A# Q) V! d( `; d- HThe etiological basis for this condition is complex
0 |2 _3 U8 N+ r4 Yand is thought to be due to a combination of both genetic. m' A' ^6 [1 F9 c) M' ~
and environmental factors that result in the disruption
6 ~5 C- ?6 S7 o9 u9 Zof normal gonadal development during fetal life. First,
  v) e- W7 q. ^6 q* i; rit was proposed that environmental chemicals with oes-
8 P+ U1 o( X; A, w2 W" |trogen-like actions could have adverse effects on male; D4 v5 q2 l# O' J
gonadal development. This has since been expanded to! n2 Z! V: k' ?& {, `
include environmental chemicals with anti-androgen( C1 K' k1 K+ g; f
actions and it is now thought that an imbalance between
+ x  R' {: c3 a+ P7 Z8 w* nandrogen and oestrogen activity is the key mechanism by
9 g, \5 a, }/ b6 nwhich exposure to endocrine disrupting chemicals (EDCs)' K& U0 F8 M; p, E4 D, L$ o, j. y
results in the development of TDS and male reproductive4 u2 K! v; D! S8 }! N+ B
tract abnormalities (5) .+ X+ z+ x1 F' w0 x
With the increasing use of environmental chemicals,
* ^4 z' }3 n# n+ n+ \* W# Kan attempt was made to establish the normal stretched
" w7 Y. q2 O, C0 ^penile length as well as the prevalence of male genital; D, O8 Y0 G) N! M$ U+ N7 H
anomalies in full-term neonates and whether there is an
7 `9 p/ W- s8 }& A6 w/ \+ binfluence of prenatal parental exposure to potential EDCs
' {: i- K4 a9 ~0 i( fon these parameters.2 [0 D7 n. J+ V& t3 w
Brought to you by | University of California - San Francisco
0 S2 ~/ a$ ^  \* W8 O( hAuthenticated2 b1 Z; C3 F4 J8 d/ @$ E4 z( O$ E9 L
Download Date | 2/18/15 4:26 AM
* \9 j8 f  L  w- g+ g/ f510 El Kholy et al.: Penile length and male genital anomalies! W6 U; q  d- E6 j
Subjects and methods/ D  |2 Z: ^& p1 `
Study population
' q4 G6 C2 M! q1 {* k/ S3 A; OThe study was conducted as a prospective cohort study at the Univer-1 n: d) p4 Z/ M+ ]; ~
sity Hospital of Ain Shams University, Cairo, Egypt. A sample of 1000' o$ w5 V2 s5 Z# u5 g
male full-term newborns was studied.* [; u4 G- R* X( P( E
Sampling technique
/ h: t* U- V% }: Q/ j- B8 mThree days per week were selected randomly out of 7 days. In each
) ]( n5 Q$ `" yday, all male full-term deliveries were selected during the time of fi eld
5 {6 d' L* F8 l' Kstudy (12 h) during the period from March 2007 to November 2007.
/ U8 J9 [( w. ZStatistical analysis
! n5 t8 e+ p) B( aThe computer program SPSS for Windows release 11.0 (SPSS Inc.,
' c' ], l( k9 B. aChicago, IL, USA) was used for data entry and analysis. All numeric& N. h6 m" x7 Z7 d- l
variables were expressed as mean ± SD. Comparison of diff erent vari-
) i) O5 e( Q, p' h4 Y% {ables between two groups was done using the Student ’ s t-test for0 @$ P1 i  p9 ^6 N: }3 T
normally distributed variables. Comparisons of multiple groups were
' Z% f5 a+ F) Y( o( idone using analysis of variance and post hoc tests for normally dis-% |2 o  R, f  s! I0 c6 `
tributed variables. The χ 2 -test was used to compare the frequency of0 |( J. l* V7 d% I5 _3 @
qualitative variables among the diff erent groups; the Fisher exact test; u! t: r4 k- S# B4 d8 P. S% a
was performed in tables containing values < 5. The Pearson correla-. O& G& N6 g8 N  E4 X) W0 C
tion test was used for correlating various variables. For all tests, a
8 N) Z& H5 l/ Vprobability (p) < 0.05 was considered signifi cant (10) .
6 y. F( U, Q* J% b+ @% DResults4 K" V8 Q# P  q: E
Data collected
! y6 @  j* m+ o3 [/ PA researcher completed a structured questionnaire during inter-2 i: U, b" C' C; ]8 V) D9 @- ?' ^
views with the mothers. The questionnaire gathered information
7 I- {( J$ K3 A% u" H( ?- Ron the following: age of parents; residence; occupation of the
: S7 M6 v5 z+ H9 @parents; contact with insecticides and pesticides and their type and
8 ]4 e  E2 f. [" c1 Ffrequency of contact; maternal exposure to cigarette smoke during
+ q8 c+ ]# o8 I6 Z1 t0 T6 x; rpregnancy; maternal drug history during gestation; family history# x: z2 n0 a* ]* c% o
of hypospadias, cryptorchidism, or other congenital anomalies; in-# M5 r3 w% x' D# Z9 X. P
take of foods containing phytoestrogens, e.g., soy beans, olive oil,
. T" B$ d% f' |garlic, hummus, sesame seed, and their frequency; and, also, his-
7 k8 P3 D4 K/ h5 \0 {tory of in vitro fertilization or infertility (type of infertility and drugs
5 h0 H" k: f  m+ N3 t. Sgiven).
) q/ o" b: r4 C4 V: O; `1 f% L9 SEnvironmental exposure to chemicals was evaluated for its po-
6 Y  f$ {  J2 ttential of causing endocrine disruption. Chemicals were classifi ed
1 X1 x- w$ S2 K, e3 \into two groups on the basis of scientifi c evidence for their having
. E9 |0 {9 e/ [endocrine-disrupting properties: group I: evidence of endocrine dis-
" Z) v) R' e2 P8 R( _ruption high and medium exposure concern; group II: no evidence of  C! ~( [! q: d* p
endocrine disruption and low exposure concern (7) .0 I* {3 y0 W2 a' q6 i- }# [2 H/ L, S
Descriptive data
4 l/ F8 |8 ]3 ~- zThe mean age of newborns ’ fathers was 36 ± 6 years (range
0 B7 p$ {9 |0 `) N3 \: Q20 – 50 years) and that of mothers was 26 ± 5 years (range7 h, \* C. {+ v9 ?% ?  r$ \0 V
19 – 42 years). Exposure to EDs started long before preg-
6 h  K! w- t5 ]( L$ dnancy and continued throughout pregnancy. Regard-
" W- l# w1 A6 R, Ging therapeutic history during pregnancy, 99 mothers
/ I2 z! t% _, T) u2 \(9.9 % ) received progestins, 14 (1.4 % ) received insulin,! z$ h: d' G3 A8 F
6 (0.6 % ) received heparin, 4 (0.04 % ) received long-' {9 N8 f' A/ w9 B5 Q
acting penicillin, 3 (0.3 % ) received aspirin, 2 (0.2 % )# j) A' S$ L7 v- m' C$ K* f
received B2 agonist, and 1 (0.1 % ) received thyroxin,
1 B- ]7 w: K) j/ A3 N  i, R3 ]3 pwhile the rest did not receive any medications during
( L/ B; @  M3 L3 |, [& ^pregnancy except for the known multivitamins and
/ T7 w& ^4 I' o1 Z# J9 e: F& Ecalcium supplementations. In addition, family history
& p+ ^: h# t- [( }of newborns born small for gestational age was positive6 p! e5 M8 K3 e+ u
in 21 cases (2.1 % ).1 E) Q6 K6 g% I% n1 p- }- _1 Y& t2 Q
Examination
1 U  I2 G. g  _In addition to the full examination by the paediatric staff , each boy$ A1 [( V1 x, o6 H. U) M
was examined for anomalies of the external genitalia during the
! H! A, C- Q+ Dfi rst 24 h of life by one specially trained researcher. Examination
4 i- v& `3 ^1 k) t1 m% F6 x/ }! eof the genital system included measurement of stretched penile
& F8 k% d# U$ H9 k' C- q( Plength (8) and examination of external genitalia for congenital
# ?4 z% \3 q2 q3 I8 zanomalies such as cryptorchidism (9) and hypospadias. Hypospa-7 G+ M& z& Y, ~4 g' A! K' ?
dias was graded as not glanular, coronal, penile, penoscrotal, scro-7 M6 i6 i6 u, N! Y  p: x" ^
tal, or perineal according to the anatomical position. Cases of iso-
. [+ U  A% ^& j9 K* _: z7 U  q( mlated malformed foreskin without hypospadias were not included
6 D8 `! s- Q. J8 a, L1 Sas cases.! s* P3 G  s0 H- Q/ b. h
Penile length8 S8 G7 J0 Z/ S. B
Laboratory investigations* Q/ Z$ u% r: H% F
Free testosterone level was measured in 150 randomly chosen neo-
! H" N4 t8 Q9 w. I- qnates from the studied sample in the fi rst day of life (enzyme im-# \% j4 ?3 |! P
munoassay test supplied by Diagnostics Biochem Canada, Inc.,
4 q" c' k, U$ ?& \0 I: h# [& z1 GDorchester, Ontario, Canada).
/ U/ @1 ?+ d/ d% t9 bMean penile length was 3.41 ± 0.37 cm (range 2.4 – 4.6 cm).% _6 _$ x0 ~# G
A penile length < 2.5 cm was considered micropenis ( < the% `, d: L6 X0 J# `2 f1 i8 b
mean by 2.5 SD). Two cases (0.2 % ) were considered to; c; _" \7 r  @7 u' b, r6 i
have micropenis. Mean penile length was lower (p = 0.041)
4 S  G% P4 t  Q6 Oin neonates exposed to EDs (n = 81, 3.1 cm) compared to the
6 d1 R  \' e4 {* enon-exposed group (n = 919, 3.4 cm; Figure 1 ).
4 W4 X3 I) `( Y, T9 PThere was a linear relationship between penile length
% V: V% X: c8 X: Y& i* Yand the length of the newborn with a regression coef-$ g, a7 M2 x: \- B+ }
ficient of 0.05 (95 % CI 0.04 – 0.06; p < 0.0001), i.e., there2 o4 p' l. F3 G3 t0 v8 |
was an increase of 0.05 cm for each unit increase in length
9 A5 [" K8 x" X% T" ^(cm). Similarly, there was a linear relationship between: r: X' Z5 t! h# R
penile length and the weight of the newborn with a regres-
( X5 K! j) m! k4 I! J7 b  ]% E# Csion coefficient of 0.14 (95 % CI 0.09 – 0.18; p < 0.0001), i.e.,
. {3 Z  X( W3 D* g4 v7 @8 q* W( ]there was an increase of 0.14 cm for each unit increase in$ t9 A8 a+ W3 F8 ~4 S# t
weight (kg).
8 ?* Z& Q; g( t' F  X: `Brought to you by | University of California - San Francisco/ ^# j; S( o8 L0 m6 K3 M
Authenticated) T; G9 K) A) V- P! p* w& e6 y8 j6 S
Download Date | 2/18/15 4:26 AM
- G% `6 O1 w5 `7 {- c( DEl Kholy et al.: Penile length and male genital anomalies 511
1 k( C/ b- q" y1 p3 E% O. p3.45
' ?9 y6 X: B  Y7 d- t' ~/ ^3.40+ M, w/ m3 N6 t! h6 b% [/ h
3.35' l1 G$ O4 F* }* D
3.30
6 z/ V) c1 B; W! I$ ?3.253 v/ X; g" b1 s- N
3.20! m5 M  T/ X" ^/ q# s
3.15
7 N  Y& j+ k  ]3.104 I# h$ S& W: F1 {3 V' B; D
3.05+ d# t* F  Y6 v& X, @8 d) z$ J0 O1 z
3.00
; ]9 ~: I/ ?" ~8 G4 v2.95" T5 Z# b# W) j8 x
2.90
3 J3 D2 m. y7 y( {Mean% _: u* t! a, J8 l% z
penile! m6 U$ Q! v* s& B3 D: q& f
length* X5 r9 i$ Y& H  Z( q1 H3 C& I9 a0 d
an odds ratio of 6 (95 % CI 2 – 16), i.e., the exposed persons
9 ^( C0 [3 \1 W6 y/ _. l' Rwere six times more likely to develop anomalies than
7 M9 B; M; J/ `2 Q" Sthose not exposed (Table 1 ).) j' f0 V6 c4 _5 [; a
Genital anomalies were detected in the offspring" `* l( k" Z# E$ a
of those exposed to chlorinated hydrocarbons (9.52 % ),
* a) y9 y7 b% f7 kphthalate esters (8.70 % ), and heavy metals (6.25 % ). In
* N9 q& J( }- I5 fcontrast, none of the newborns exposed to phenols had
1 \* M9 I$ Q  e# t) b9 qgenital anomalies (Table 2 ).
* Y9 j3 }" ?, G. f5 |- HExposed% D/ ~# g0 @& O- W; u9 m+ r
Non exposed6 B+ M" T, \  K4 p
Penile lengths according to exposure to endocrine& R* Y) E, S- C1 k
Figure 1 disruptors.
2 B, \. c/ H4 ]$ q2 m2 \8 pSerum free testosterone levels
7 I- y7 O7 L% W/ C4 x1 ?Exposure to cigarette smoke and progestins
9 ~8 D" r+ o8 {( jduring the first trimester* Y* V; G) ~2 e2 u8 Z6 |6 o
None of the mothers in the study was an active smoker;. a3 |' v0 j7 i8 M
350 were only exposed through passive smoking. There
' t, u# R% p  b! y/ j, a) ~6 Bwas no difference between rates of anomalies among
  r: o9 f" [. l) {6 V8 _those exposed to cigarette smoke when compared to those. C% t4 e3 T* }) B
not exposed (1.1 % vs. 2.2 % ). Similarly, there was no differ-
0 g9 D7 @$ i: k2 d* U8 h. \: l, Bence between the rates of anomalies among those exposed# e' ?' H7 x1 k2 `- g, L( {9 P
to progestins during the first trimester when compared to; Q3 F: z5 C! `9 w7 B$ o& p
the non-exposed ones (2 % vs. 1.8 % ).
2 u9 G9 \( K; ^7 QIn the first day of life, serum free testosterone levels) H+ `) w3 w% u& ^5 D0 {
ranged between 7.2 and 151 pg/mL (mean 61.9 ± 38.4 pg/mL;
3 ^+ {$ e! z- t9 U1 m" `6 S4 }/ Nmedian 60 pg/mL). There was a linear relationship$ F! N' H+ U4 L; Y4 U4 G% N! z
between penile length and testosterone level of the
; o6 b: t4 E$ h0 O) Pnewborn with a regression coefficient of 0.002 (95 % CI
+ w- x3 l1 F% }( N$ u1 \0.0004 – 0.003; p = 0.01), i.e., there was an increase of 0.2 cm6 s1 P: y2 j$ h
in penile length per 100 pg/mL increase in testosterone
5 e! v  ~! j. m. f; [$ i  @level. Moreover, serum testosterone level was significantly" a: ?( f/ N5 b* p
lower in newborns exposed to EDs (49.50 ± 22.3 pg/mL)
3 ^4 j; C  z" p6 x3 }) vthan in the non-exposed group (72.20 ± 31.20 pg/mL;
' a/ Y7 Z: O% Z( o1 u, ^/ o$ d  Pp < 0.01).
( `7 m3 T) \* a' r, }4 VTable 1 Frequency of genital anomalies according to type of
2 k  w% W. O* ]2 Rexposure to endocrine disruptors.
4 u9 _& d: T) A  m8 J" Q) s4 NExposure to endocrine5 U- u5 V& U  f8 i, X! u! V! c8 _
disruptors
# k! Y1 P% q, VPrevalence of genital anomalies3 j! V2 ^" N; u" ~) G2 }/ T; ^6 n
Anomalies Total! W* |/ z( R1 v
Negative Positive5 {1 t; s0 A2 R- t# Q0 C& E
Negative exposure 908 11 919
: }7 q5 c0 T, ^: t: D98.8 % 1.2 % 100.0 %* A" g) l$ h. `4 ~
Positive exposure 75 6 81
. K* {  _1 }+ a/ p8 R0 \' _92.6 % 7.4 % 100.0 %
; r) [3 y8 x) A! `Total 983 17 10001 x7 n# ~2 s; }7 {0 l$ J' `
98.3 % 1.7 % 100.0 %
* n3 G; V% F9 _& r& A: {& Mχ 2 = 25.05, p < 0.0001.
2 ^( n/ F  }5 n# V  ^$ \9 YOver the study period, the birth prevalence of genital
7 x% K0 `& B) [. E2 v( Lanomalies was 1.8 % , i.e., 18/1000 live birth. Hypospadias4 ]2 h' v# U3 B* S* \/ X4 I
accounted for 83.33 % of the cases. Fourteen had glanu-
! W% x1 E  p4 Z; v+ ?lar hypospadias and one had coronal hypospadias. One. [3 e+ D/ f1 {
had penile torsion and another had penile chordee. Right-" p: i2 o5 `! ]% e( _% Q
sided cryptorchidism was present in one newborn.4 I7 i# u/ ^5 w
Exposure to EDCs
, \- @5 J- `" w0 A0 i  I  }! kAmong the whole sample, 81 newborns (8.10 % ) were
. g2 T+ p4 l5 K$ oexposed to EDs. The duration of exposure varied from
5 I, x8 \; ?% r% y- ^" H; J2 to 32 years with a frequency of exposure ranging from
; _$ x2 a9 @& w* G8 aweekly to 2 – 3 months per year.- N/ s$ r& P& ], @% o
There was a significantly higher rate of anomalies4 p2 c( ?5 ^4 [# }6 Z
among those who were exposed to EDs when compared
7 R& ?9 R$ k3 m0 C8 B* E; @( e. jto non-exposed newborns (7.4 % vs. 1.2 % ; p < 0.0001), with2 F1 V$ G5 t: ~! S' y$ Q0 a6 T
Table 2 Type of endocrine disruptor and percentage of anomalies in0 J" {* A4 L( {  `
the group of neonates exposed to endocrine disruptors (n = 81).
8 m. @. q5 {8 ], ^  q: nAnomalies Total
, _. h$ [/ \" k8 X6 e' p; pNegative Positive/ q% J2 m/ Y; E; D) A; k
Chlorinated hydrocarbons (farmers) 19 2 21
2 |% [/ }- r/ a90.48 % 9.52 % 100.0 %
4 m$ V0 E2 ?" m6 u$ aHeavy metals (iron smiths, welders) 30 2 320 ~% ]9 o4 W% L! b% c, f
93.75 % 6.25 % 100.0 %
& H! I3 e( r5 `  D5 uPhthalate esters (house painters) 21 2 23
2 t) Q- ]" h4 e% z- \7 C# R' i91.30 % 8.70 % 100.0 %0 P8 Y" t( x/ }8 F/ K
Phenols (car mechanics) 5 0 5% V3 m+ _8 w& |% M# D& k) W3 q
100.0 % 0 % 100.0 %3 c+ ]& k/ h: I7 c8 |! k; c) g
Total 75 6 81) e0 I) s2 ]  M+ m
92.60 % 7.40 % 100.0 %- N4 t: @- B% M+ R
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512 El Kholy et al.: Penile length and male genital anomalies6 ]# A. ~7 R  k
Discussion  K! }! {. f: T! F  ^
Previously reported penile lengths varied from 2.86 to 3.75 cm" i" \6 D% n0 Z. _( C  _0 I5 D5 K
(11 – 16) and depended on ethnicity. In Saudi Arabia (13) ,
5 m# _4 t0 i3 |% {0 cmean newborn penile length was 3.55 ± 0.57 cm, slightly6 L% I# ]: }7 b& ]/ C5 B. {
higher than our mean value. However, the cut-off lower' a. V5 C8 R. b3 U% C  L% q5 T
limit ( – 2.5 SD) was calculated to be 2.13 cm (vs. 2.5 cm in
: G; |& z. p2 e' x+ {9 b4 Q! your cohort). This emphasizes the importance of establish-
$ w0 E1 m: {0 f  B0 H5 D0 i, {ing the normal values for each country because the normal
1 @5 W# Q6 |4 E8 N9 D" N  grange could vary markedly. In a multiethnic community,0 k, w/ c- e8 R$ Z# C
a mean length of – 2.5 SD was used for the definition of
/ G( [! R6 f- F- gmicropenis and was 2.6, 2.5, and 2.3 cm for Caucasian,& q. `  j6 i/ \; {+ k7 ~
East-Indian, and Chinese babies, respectively (p < 0.05).
) G  Y& s# C# RThis is close to the widely accepted recommendation that
/ W0 j" ^% b  h( I8 ea penile length of 2.4 – 2.5 cm be considered as the lowest" o  W' O2 o% V! x
limit for the definition of micropenis (8) . The recognition
' [4 n# F$ ^( jof micropenis is important, because it might be the only: v2 k% m* a) m# i+ \0 u0 o% O
obvious manifestation of pituitary or hypothalamic hor-
+ G; |, t: q1 _1 Z- }1 _monal deficiencies (17) .* x4 ~  v3 e5 J1 F
The timing for measurement of testosterone in new-
# `3 D! `( o( Y" Xborns is highly variable but, generally, during the first 2  h0 B* A% K6 X! ?. g
weeks of life (18) . In our study, serum testosterone level( j6 X" K0 N8 \7 k7 G
was measured in all newborns on day 1 in order to fix a4 A9 }3 B; T1 G: x# z, E
time for sample withdrawal in all newborns and, also, to
8 v* k$ n2 U: W3 H# ^8 Gmake sure that all samples were withdrawn before mothers6 S( B& \1 E" W3 q9 Y5 W# L
were discharged from the maternity hospital. We found a
# x. @+ S, q. M( H% \& Ilinear relationship between penile length and testosterone2 N, {8 H. i4 |% P2 L& p5 u
levels of newborns. Mean penile length was lower in neo-8 D" Z8 `2 ]/ T- W1 U) ?
nates exposed to EDs compared to the non-exposed group,( ~- W3 N3 g( A; k. X' [, c% i& n
which could be related to the lower testosterone levels in
7 K1 x) \- S4 k4 fthe exposed group. The etiology of testicular dysgenesis
8 [: s! k+ A5 f3 @syndrome (TDS) is suspected to be related to genetic and/or* G" ?4 J% v' L, a3 @' \
environmental factors, including EDs. Few human studies
" K9 S! E7 Q, |/ }' H  m4 q( }. Khave found associations/correlations between EDs, includ-
  C4 f5 }& Q' X6 N9 _ing phthalates, and the different TDS components (18) .& i5 a* x- ~8 V# d' B( E8 Y2 w
Some reports have suggested an increase in hypo-. G3 s# T* I: z, k5 \* z
spadias rates during the period 1960 – 1990 in European6 \  g. x" O$ t2 ~+ t
and US registries (19 – 23) . There are large geographical
$ W: y- e; h* Pdifferences in reported hypospadias rates, ranging from8 F8 g; b1 }& B) _7 h/ Z* D
2.0 to 39.7/10,000 live births (23 – 25) . Several explanations
5 @/ t+ g* f) Yhave been proposed for the increasing trends and geo-
- U9 n/ {6 x2 |0 @graphical differences. As male sexual differentiation is9 \+ ~! [4 A$ o9 g' e3 j+ b. K
critically dependent on normal androgen concentrations,
3 X5 a; i) k. F1 g; Iincreased exposure to environmental factors affecting
+ _* d9 I7 S+ @androgen homeostasis during fetal life (e.g., EDs with
" Q* _  q% ]" S# K* qestrogenic or anti-androgenic properties) may cause
( F% O' n4 w2 U. v+ Z/ _! t( phypospadias (3, 4) .
$ j, Q, C6 @; q3 O$ v/ i- {In Western Australia, the average prevalence of hypo-% Z% V5 k) r5 ^" R6 c
spadias in male infants was 67.7 per 10,000 male births.
, |6 y* L' @; r, P1 \! o' F& [When applying the EUROCAT definition (24), the average
% {7 G0 h1 S5 p5 Z& V0 V. Y7 wprevalence of hypospadias during 1980 – 2000 was 21.8 per
! ?# M+ u" s3 N  m10,000 births and the average annual prevalence increased. b6 x9 h( P  n5 k0 J
significantly over the study period by 2.2 % per year. The5 d8 \( d4 K0 w$ p
prevalence of hypospadias in this study was much higher; Y& R4 Z! @& x( t: W. ?% e
at 150 per 10,000; by excluding glanular hypospadias, the7 n. f5 N( l7 Y. M4 b8 v; J7 X
prevalence fell sharply to 10 per 10,000 (26) .
+ {5 z4 A6 u* X! U6 m% n2 MWe found a higher rate of anomalies among newborns' {( I! e" k6 P6 F. @
exposed to EDs when compared to non-exposed newborns
3 Z2 U% |8 z/ G(7.4 % vs. 1.2 % ); this raises the issue that environmental
; b% S& Z' ]1 Y3 @. r% [+ C' [; hpollution might play a role in causing these anomalies.0 |0 F; U" W8 ^- r" ]6 O+ U
Within the last decade, several epidemiologic studies  {* e% a! p3 E, `6 m) j
have suggested environmental factors as a possible cause# W, t& A; D) p
for the observed increased incidence of abnormalities in
# t& L3 F' _$ v$ N9 `male reproductive health (27) . Parental environmental/
( }* r" q0 A6 U: A, w8 J$ Soccupational exposure to EDs before/during pregnancy! @1 i1 N! D, L( o* z* [3 ?, h) b
indicates that fetal contamination may be a risk factor for3 y( J* W) G) m9 m. s
the development of male external genital malformation9 Z" G7 ?- F9 I0 ^0 i
(27 – 29) .
- Z+ V2 A1 K; W  R% x9 oReceived October 25, 2012; accepted January 27, 2013; previously5 Y4 A% v: p% y+ q0 M7 l
published online March 18, 2013
+ [  `/ f, t% T5 D2 t# f! g$ BReferences) J, T7 X5 d/ Z, f
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according to ethnicity ? Horm Res 2001;55:278 – 81.
+ J4 ?" [  p: {* oBrought to you by | University of California - San Francisco
5 p" D* B3 t% d8 VAuthenticated
, \4 v  D% o/ Y! I1 v& o# lDownload Date | 2/18/15 4:26 AM
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US surveillance systems. Pediatrics 1997;100:831 – 4.6 H$ ]7 Q4 w) ]" L6 v2 i
penile length in newborn and infants. BJU Int 1999;84 : 1093 – 4.0 a0 j( y! b+ i- W0 ]8 b$ @6 Q- M& o
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Genital standards for south Indian male newborns. Indian J3 {8 D* D7 L: {
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; C4 E$ E& S6 Y; ^7 ~penile size in the newborn infants. J Pediatr 1975;87:663 – 4.; ^1 M8 C5 y4 F, s3 E. f! t5 Z
12. Ozbey H, Temiz A, Salman T. A simple method for measuring+ A4 w& Q5 F5 f, r4 j5 A2 v& B
13. Al-Herbish AS. Standard penile size for normal full term
2 l! a: T! v7 L/ E" D7 Xnewborns in the Saudi population. Saudi Med J 2002;23:314 – 6.* c" h( p1 ]: v7 r) B0 x# d
14. Lian WB, Lee WR, Ho LY. Penile length of newborns in Singapore.
- B+ N$ y4 M6 A" I15. Pediatr 1995;62:593 – 6.
3 K, p+ k8 a9 R9 l4 F' o" y( E16. Boas M, Boisen KA, Virtanen HE, Kaleva M, Suomi AM, et al.
4 O6 M' U' ^5 U9 a  E4 @3 }% [+ u% ~2 _% |Postnatal penile length and growth rate correlate to serum
: }* Y  M5 D1 e2 U/ ytestosterone levels: a longitudinal study of 1962 normal boys.
, u, _; M. G7 B2 {' J4 x  s7 y5 u' oEur J Endocrinol 2006;154:125 – 9.6 l  u7 G) D; l1 J2 C+ i( ?
17. Camurdan AD, Oz MO, Ilhan MN, Camurdan OM, Sahin F,0 o$ q, C6 X  i! ?& B
et al. Current stretched penile length: cross-sectional study6 O* b. m/ v( B$ R
of 1040 healthy Turkish children aged 0 to 5 years. Urology
3 O$ m3 A3 Z: E3 F( a6 `2007;70:572 – 5.
0 K  [" ]! ~% b4 ?) G6 H; w18. Bay K, Asklund C, Skakkebaek NE, Andersson AM. Testicular* q% ]" y: f' G
dysgenesis syndrome: possible role of endocrine disruptors.
# n6 H# M2 t, d+ _' X" YBest Pract Res Clin Endocrinol Metab 2006;20:77 – 90.
, x* j6 U- Y2 u! j19. Czeizel A. Increasing trends in congenital malformations of male4 |6 }2 z! B7 r+ A% A# d9 ?" R& ^
external genitalia. Lancet 1985;i:462 – 3.% h% w2 U& Q# W
20. Matlai P, Beral V. Trends in congenital malformations of external0 ]6 T' s7 e0 W) W) k1 j( A7 p
genitalia. Lancet 1985;i:108.
6 ]; ^6 s. M% A& d23. Paulozzi LJ. International trends in rates of hypospadias. J4 m. ?* ?; N( G
and cryptorchidism. Environ Health Perspect 1999;107:2 f2 {6 I5 Y9 A) n0 n2 C/ d$ [7 g
297 – 302.
( B: U- D+ b# c  T  A9 U" s- G24. EUROCAT Working Group. EUROCAT report 7. 15 years of
, @; Y8 k5 H% f' w8 `surveillance of congenital anomalies in Europe 1980 – 1994.
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Pasteur, 1997.. m$ h( U7 E$ @
25. Toppari J, Kaleva M, Virtanen HE. Trends in the incidence
, v/ n+ T6 m" lof cryptorchidism and hypospadias, and methodological
& I% ]# {7 V6 Slimitations of registry-based data. Hum Reprod Update
0 p  z# O5 C* O* W2001;7:282 – 6.
! k7 E( x* u; j26. Nassar N, Bower C, Barker A. Increasing prevalence of
5 Q: R6 E, o5 {6 D2 \5 T2 yhypospadias in Western Australia, 1980 – 2000. Arch Dis Child
9 g& n8 i2 _# f$ r2007;92:580 – 4.
0 n6 d2 i7 V9 \27. Wang MH, Baskin LS. Endocrine disruptors, genital
5 W- m6 F% J% bdevelopment, and hypospadias. J Androl 2008;29:499 – 505.: C( u3 W1 H8 J3 {+ L6 o1 a2 ?( d
28. Morales-Su á rez-Varela MM, Toft GV, Jensen MS, Ramlau-Hansen( n5 N, u+ @7 z1 K, _
C, Linda Kaerlev L, et al. Parental occupational exposure to
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mations: a study in the Danish National Birth Cohort Study.8 _! V& o' D. H( E/ }% [  m
Environ Health 2011;10:3.2 s8 X4 o, S/ B( F( c
29. Gaspari L, Sampaio DR, Paris F, Audran F, Orsini M, et al. High
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2012;35:253 – 64.
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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) h# w: G& R7 H7 g" q
GONADOTROPIN
# t; Y0 n; I  u$ k3 R5 |RICHARD C. KLUGO* AND JOSEPH C. CERNY
. [& S) W) J" h. ^# `5 J  `. iFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 l$ B7 a; s: X# e0 t+ C4 vABSTRACT
" B, M  t0 K* D5 L1 ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 m4 r, p5 Q. W1 C( S, T6 iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) O5 ]( j/ t8 ^' |0 ~7 F- }tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 Z' e) t  R) P# A# T
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent" c+ i+ q: I4 O: h8 Z6 ^: r- y+ ?: m
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
1 t5 d6 p; u1 v5 O0 D( M6 [increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! B; t: B: ^, l; k5 O  i
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
0 I, ]9 A6 H% H; [occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, F) `% s3 S0 {9 lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& d5 b2 A: s2 d8 \9 Z* k) |growth. The response appears to be greater in younger children, which is consistent with previ-
4 l8 H5 D; U6 D( Z3 Q/ l& j: Pously published studies of age-related 5 reductase activity.
1 k- M3 y5 i- t* R% H4 w1 TChildren with microphallus regardless of its etiology will
% _6 A0 ^+ y8 L& P$ lrequire augmentation or consideration for alteration of exter-
0 ]0 U% l0 \- m& R4 pnal genitalia. In many instances urethroplasty for hypo-
* ]/ Q& i5 ]6 z! B+ ]: S- [spadias is easier with previous stimulation of phallic growth.
2 T2 v% c8 t0 y9 o# c# uThe use of testosterone administered parenterally or topically0 B' L# O& Q( x; g! n& ~! \" X# f% z
has produced effective phallic growth. 1- 3 The mechanism of' W+ k2 l6 b- n* q; K
response has been considered as local or systemic. With this
0 P& m( f9 p$ B* z6 J# l9 uin mind we studied 5 children with microphallus for response
1 s2 p: r8 @( ?/ J- K: p8 N* H# _to gonadotropin and to topical testosterone independently./ }$ x! v$ ?2 F7 ^
MATERIALS AND METHODS8 ^% J/ B- V( w5 `9 J2 Z
Five 46 XY male subjects between 3 and 17 years old were
7 D1 i' ?$ L; u: U5 H, A8 Jevaluated for serum testosterone levels and hypothalamic, n, E( h8 |6 c0 L* B# F. k/ B8 H
function. Of these 5 boys 2 were considered to have Kallmann's& E  u" ]2 J! P( Q
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 J# ]) l, [( C
lamic deficiency. After evaluation of response to luteinizing
9 ~* U' _, b# R# d6 I" uhormone-releasing hormone these patients were treated with
( W2 t; M) Y6 k1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: E. t+ o4 ]. `$ I# oafter completion of gonadotropin therapy 10 per cent topical
2 v# I, a8 x# j  `. etestosterone was applied to the phallus twice daily for 3 weeks.8 ?" G! ~  C2 }& O
Serum testosterone, luteinizing hormone and follicle-stimulat-5 B" {  r9 \! U4 j6 G
ing hormone were monitored before, during and after comple-" M9 y5 L0 U+ ]
tion of each phase of therapy. Penile stretch length was9 [5 j6 s- E/ N2 w3 m
obtained by measuring from the symphysis pubis to the tip of
8 \( ?$ P' U9 m2 b3 u. \& G% bthe glans. Penile circumferential (girth) measurements were# F- ^; |/ g5 L$ e! Q
obtained using an orthopedic digital measuring device (see
. I* c: G2 A4 s5 J7 q; _figure).
% A# G" A# J; Y2 ?RESULTS
, h; @9 w8 i" HSerum testosterone increased moderately to levels between
: D  y% {, A% l' s50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-# \5 P4 H" x  \7 I2 h* G/ t
terone levels with topical testosterone remained near pre-
: s, ^5 E7 ]. w1 I, k" utreatment levels (35 ng./dl.) or were elevated to similar levels; n8 R  O% n% c6 ]; C7 }7 j- {3 [
developed after gonadotropin therapy (96 ng./dl.). Higher
4 H/ p& C# |4 @; K* \, ]serum levels were noted in older patients (12 and 17 years old),0 I1 ?: D6 f+ Z5 t+ o
while lower levels persisted in younger patients (4, 8, and 10
, ?: V+ U4 S. c9 s; F0 cyears old) (see table). Despite absence of profound alterations
6 }7 C. o1 b, Y. S# W) hof serum testosterone the topical therapy provided a greater
, z# J$ n6 o6 d2 o. f: ~& f  A  HAccepted for publication July 1, 1977. ·
  d/ @! G4 c5 U5 o9 ARead at annual meeting of American Urological Association,
$ K6 [& t. j  nChicago, Illinois, April 24-28, 1977.' M1 Y3 P, m1 ], G
* Requests for reprints: Division of Urology, Henry Ford Hospital,
) V# v0 d) R+ h6 s& s1 a5 f0 b2799 W. Grand Blvd., Detroit, Michigan 48202./ W- K9 W& H0 @5 ]
improvement in phallic growth compared to gonadotropin.
" e( g/ |% z8 L! ~Average phallic growth with gonadotropin was 14.3 per cent
. ?, U3 Q+ ~- ^2 i6 tincrease in length and 5.0 per cent increase of girth. Topical
0 l( z$ m5 M' f! M; L' \" Utestosterone produced a 60.0 per cent increase of phallic length8 k8 G2 u5 u. R( L
and 52.9 per cent increase of girth (circumference). The
7 |6 I" t$ a" l* r3 r& Sresponse to topical testosterone was greatest in children be-
3 L' Z7 z' s6 L% N( \tween 4 and 8 years old, with a gradual decrease to age 17
1 Z4 I) G1 C9 ]5 `7 Dyears (see table)." {8 R1 B& P- H' u* E5 A
DISCUSSION0 e% V$ G" M  Z& o$ p+ a( u6 w
Topical testosterone has been used effectively by other! Y1 W. [! O3 k; k( [/ I( \& M9 C
clinicians but its mode of action remains controversial. Im-
, O+ c1 w, m: j" Z/ pmergut and associates reported an excellent growth response
9 `) I% F  p+ E7 Z+ |# n1 ~to topical testosterone with low levels of serum testosterone,
- }) n; R6 i& B/ b$ asuggesting a local effect.1 Others have obtained growth re-$ L4 z, ^7 d5 z8 |
sponse with high. levels of serum testosterone after topical+ u0 g6 r* P* X: H& n
administration, suggesting a systemic response. 3 The use of
4 G0 P! x5 }! _4 h' U( i1 h  F% sgonadotropin to obtain levels of serum testosterone compara-
& {- P7 }! L) K% @- r& [ble to levels obtained with topical testosterone would seem to
. X+ g$ j) q$ H6 Hprovide a means to compare the relative effectiveness of
6 C! H+ U; [& L4 {1 \0 @topical testosterone to systemic testosterone effect. It cer-0 \% t6 m' Z- b  g0 o
tainly has been established that gonadotropin as well as par-( @7 `. F! d2 c' {
enteral testosterone administration will produce genital$ U3 s* {5 d" a% \* X- `! T
growth. Our report shows that the growth of the phallus was
( r4 h) ^: \- r* _- H# W; Q# Lsignificantly greater with topical applications than with go-( S9 c, u. b) `3 |
nadotropin, particularly in children less than 10 years old.
1 k+ P6 ^9 g. b' G4 `" hThe levels of serum testosterone remained similar or lower" u  K( }% }- C3 N0 e7 I
than with gonadotropin during therapy, suggesting that topi-
, ?; E; P2 D8 [. {- u$ N+ O; c* @cal application produces genital growth by its local effect as
/ N+ z' Y/ ~+ C) E' Kwell as its systemic effect.- z8 R) M: \. t. d0 H8 w
Review of our patients and their growth response related to  A. `6 `/ `8 ?7 L. e1 u& X) R9 {* C
age shows a greater growth response at an earlier age. This is2 J4 w; J0 q% I) ~; c! p2 z. R
consistent with the findings of Wilson and Walker, who
# ?: q& l0 G3 i- jreported an increased conversion of testosterone to dihydrotes-" w, ^! t2 L$ s9 l
tosterone in the foreskin of neonates and infants.4 This activ-
3 F5 X. z) g$ g5 m; B: Bity gradually decreases with age until puberty when it ap-
( }, R2 R# t; h+ eproaches the same level of activity as peripheral skin. It may8 H/ T$ j) W# R4 h
well be that absorption of testosterone is less when applied at
% F  M3 P5 w# z8 D$ e- C- l0 n9 n6 Ran earlier age as suggested by lower serum levels in children6 A4 J8 l0 ]- i! w$ R7 D
less than 10 years old. This fact may be explained by the
: K3 c9 s* w! I- ?# dgreater ability of phallic skin to convert testosterone to dihy-
$ j9 y5 [# Q3 I$ H! {2 Hdrotestosterone at this age. Conversely, serum levels in older
" b( y: v* a5 e9 u3 h- a( z+ l3 ?patients were higher, possibly because of decreased local
" j7 }* {4 `, H/ S8 L/ C# M% p6671 S* q& q& n2 ^; ~  O
668 KLUGO AND CERNY5 x$ k: I4 \8 S0 j1 L0 J* Z1 i
Pt. Age
, }/ {# F7 L* R  c' R: u(yrs.)# F) o1 Q6 f7 G0 d4 C; c( i; y" d
Serum Testosterone Phallus (cm.) Change Length& L2 a1 L4 R5 v& ?: D
(ng./dl.) Girth x Length (%)
0 `( a! O8 y: i% w2 D4  C: N  K! k5 F% b/ \( ~" ^
87 f- S. i* K( A2 @# t
10
' r/ L5 m1 V3 n% k, }$ G7 y* x12
" F* T1 R7 |& x0 x# l8 C! z17
+ F: O( g: p/ E6 b' d- W9 w+ f% YGonadotropin" u& o1 E' a; z/ u$ Y) k( ]! v" D
71.6 2.0 X 3 16.60 M+ l; e8 e3 x, C3 u
50.4 4.0 X 5.0 20.0: G) r1 `, Y4 C/ J8 L
22.0 4.5 X 4.0 25.04 U" A/ q2 K- I. w
84.6 4.0 X 4.5 11.16 b2 U- ^# H; O6 ?" r4 ]
85.9 4.5 X 5.5 9.00 G" x0 D9 ^: j; ^* L. o9 d  h/ U$ I
Av. 14.3
1 L3 D0 H8 |8 P4 ~* b5 {7 s4
. _/ L1 t/ R' l8, \) `) b! K4 c+ d2 y3 o$ w& K$ ~
108 h7 @1 d$ D5 F5 T
12
# g' w. ~, @* g( s  p- Y$ v17
/ b" Y4 F6 V' u. }% STopical testosterone4 T4 d$ y: a. I" G  p% K! ^
34.6 4.5 X 6.5 85
# ]8 J7 s$ e  _$ d% D4 R" C/ a38.8 6.0 X 8.5 70+ L% L  G5 K/ b9 u
40.0 6.0 X 6.5 62.5: t+ l7 R( l+ O5 k- V
93.6 6.0 X 7.0 55.5# r: [0 ~) c8 n1 z* I) }! p3 U! B- l
95.0 6.5 X 7.0 27.2
! X% y3 `6 G" T" s; w) F6 h5 F2 ]# @4 QAv. 60.0
. u% P4 d3 t0 d9 V9 E3 m0 xavailable testosterone. Again, emphasis should be placed on
& v/ c  T' _% K' g; J2 ?/ Gearly therapy when lower levels of testosterone appear to# _6 [1 R% z6 q/ I
provide the best responses. The earlier therapy is instituted
3 X, S! Z; \$ E" h4 mthe more likely there will be an excellent response with low
1 s( V! v5 v; ^/ y, Userum levels. Response occurs throughout adolescence as% o% r/ _" d2 p4 C: N/ N- F
noted in nomograms of phallic growth. 7 The actual response
8 f, l7 u( T8 |! [9 c0 R2 M& k; Sto a given serum level of testosterone is much greater at birth
; T( y! S' w; A" h( Q7 H7 Y+ Z. @and gradually decreases as boys reach puberty. This is most
2 |0 m- f* U  \2 {) q# c1 ~  a7 Ilikely related to the conversion of testosterone to dihydrotes-
# g' a- c& ?$ Ztosterone and correlates well with the studies of testosterone
: n3 S7 Z4 H& I6 nconversion in foreskin at various ages.
) n' I6 V# u7 y: w& ~The question arises regarding early treatment as to whether8 I) Q5 P' f; W# i$ \
one might sacrifice ultimate potential growth as with acceler-  i3 z4 ~8 Y. l
ated bone growth. The situation appears quite the reverse, q' Z7 Y+ G' q* \
with phallic response. If the early growth period is not used
/ [. N3 Y' s4 {6 k" Zwhen 5a reductase activity is greatest then potential growth- ^% v  w0 B. U& A* o
may be lost. We have not observed any regression of growth% ~4 N8 Y, z5 X3 U- f/ I9 y
attained with topical or gonadotropin therapy. It may well+ R+ r- q% O9 q$ y5 s' Z! v
be that some patients will show little or no response to any
$ C$ R# p/ G7 M, Fform of therapy. This would suggest a defect in the ability to
) Q6 M+ [6 R1 p0 ^3 r3 y7 |convert testosterone to dihydrotestosterone and indicate that- h9 G2 J- z3 ~0 |5 o; j
phallic and peripheral skin, and subcutaneous tissue should
9 k* J9 G; n% r) Hbe compared for 5a reductase activity.; P& j: R$ X$ n* c* k2 k& A
A, loop enlarges to measure penile girth in millimeters. B,7 N: R3 F  z( W2 b
example of penile girth computed easily and accurately.
$ J/ k; L1 {4 x% V1 g1 Bconversion of testosterone to dihydrotestosterone. It is in this
) S0 b/ M$ d( d5 s) C. Eolder group that others have noted high levels of serum7 N" {! B4 G/ o3 ]
testosterone with topical application. It would also appear' |( C9 Z1 I$ F" X- o3 B" \
that phallic response during puberty is related directly to the  K! C; U$ ~: ~: \+ a) e
serum testosterone level. There also is other evidence of local# o0 T' U: j, y, v; k: @
response to testosterone with hair growth and with spermato-
7 U7 p; I- u" p& Jgenesis. 5• 6
) A' }2 e) m+ x" |Administration of larger doses of gonadotropin or systemic
# [5 N3 y4 i' J! Z8 {testosterone, as well as topical applications that produce
+ c' q; T: q4 n9 A6 Rhigher levels of serum testosterone (150 to 900 ng./dl.), will- `3 ~/ D6 i0 W; b; Z) p
also produce phallic growth but risks accelerated skeletal) Y8 V4 L. m, K4 v
maturation even after stopping treatment. It would appear4 m& S+ f! u9 x/ r4 V3 D: P7 m6 R
that this may be avoided by topical applications of testosterone
5 r" t0 M& L" k+ Oand monitoring of serum testosterone. Even with this control
: j2 _# `8 D$ C. e4 E: [( ^the duration of our therapy did not exceed 3 weeks at any
0 F; n1 z& Z/ f4 ^0 k& Atime. It is apparent that the prepuberal male subject may
" G4 q/ k9 N' a' ?suffer accelerated bone growth with testosterone levels near
" K* K( r! [! j6 h1 E200 ng./dl. When skeletal maturation is complete the level of
1 j% l- n; O4 a- @" \serum testosterone can be maintained in the 700 to 1,300 ng./4 F& q9 ^! V. u: f
dl. range to stimulate phallic growth and secondary sexual
4 {# U3 W& V) m1 h( e) i3 V1 mchanges. Therefore, after skeletal maturation parenteral tes-
5 }6 q9 U2 n! W8 {  w2 \) Dtosterone may be used to advantage. Before skeletal matura-
! Q& Q, b+ J0 |6 Q8 v% r' F, L+ Ution care must be taken to avoid maintaining levels of serum" d. k7 d1 z1 S! |9 y
testosterone more than 100 ng./dl. Low-dose gonadotropin7 R, q, i/ d4 u: W  ]0 m9 e) Q
depends upon intrinsic testicular activity and may require
5 [5 }' Z" e8 T( F/ c: Jprolonged administration for any response.* k) t% C# P* e
Alternately, topical testosterone does not depend upon tes-8 h, H6 q. G; @/ ^7 o3 I, z4 p
ticular function and may provide a more constant level of
1 U+ q/ k% d1 i3 s+ kREFERENCES
4 @- F5 P0 o: Y$ C3 I6 N6 j1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; X$ D% i) f+ T  j0 Q9 V) w
R.: The local application of testosterone cream to the prepub-
0 h" k  G& K1 b1 O- w% Uertal phallus. J. Urol., 105: 905, 1971.% \- i& G9 n# a0 K
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone/ ]  Z# o, Y5 L5 x9 @7 Q
treatment for micropenis during early childhood. J. Pediat.,  B4 L: i5 W& F- |2 R' {
83: 247, 1973.
- Q3 G# |! {- y, f/ Q8 G3 r% Y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 h* X& M. U$ L, N  tone therapy for penile growth. Urology, 6: 708, 1975.
4 E# S$ O$ G6 P- U% B7 l4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 H; x7 P' J; B! P6 K& Fto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
( k; w6 n! o5 K1 xskin slices of man. J. Clin. Invest., 48: 371, 1969.
3 Y5 g3 a* Z5 S8 @! l5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 i8 ?2 K" J" }) A9 @) n9 |- Q6 _5 k
by topical application of androgens. J.A.M.A., 191: 521, 1965.( O; A, s1 `, g  n
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% D: W4 \0 u+ Z
androgenic effect of interstitial cell tumor of the testis. J.7 C6 U( Z, P8 E' ~+ C" h! q
Urol., 104: 774, 1970.
& f% s0 m/ U! E, H" K6 O. ~7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 c& ?' ^( T, o- P! x. stion in the male genitalia from birth to maturity. J. Urol., 48:
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