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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND ~8 ~9 |1 h, l W
GONADOTROPIN
1 l2 a0 J' u4 `RICHARD C. KLUGO* AND JOSEPH C. CERNY2 r/ ? X* p5 H+ H+ d! c
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 r6 d9 y4 f# h- F+ r1 R, \ABSTRACT: [. j8 i; z" ~+ x$ d
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 c H8 I' P0 M/ k8 O* A. W4 zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( T {: o" A, l: \+ o2 a. `tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! D* h4 c5 X8 C+ D& S0 f- acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 J) r& L9 l/ `; `( m! t+ E+ z* r
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ N* n* {: O" b5 Q& ~9 H' r+ |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, O! q5 m4 s, \6 rincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, w9 C6 a, b1 Woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 }- S s6 f- p! A) p: N" K. Zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, Z6 R! M( n* x' K0 L
growth. The response appears to be greater in younger children, which is consistent with previ-
' }" m' L# W4 K9 h& i2 H# gously published studies of age-related 5 reductase activity.
4 {. Z" o1 w8 _. C/ L" oChildren with microphallus regardless of its etiology will" y; p6 t7 `. [1 F
require augmentation or consideration for alteration of exter-
$ `" {! x: O! E$ ^nal genitalia. In many instances urethroplasty for hypo-
( ]" b Y" B+ h$ \& E9 vspadias is easier with previous stimulation of phallic growth.+ y1 N8 V6 ]. p7 {; C
The use of testosterone administered parenterally or topically
& G% ?* S; a: i6 S& _' a: }0 ihas produced effective phallic growth. 1- 3 The mechanism of; L: a8 O7 z" J9 N/ U! } v: T% `
response has been considered as local or systemic. With this- b- \& D" [! V+ F1 N% V
in mind we studied 5 children with microphallus for response; Y$ F1 R9 k3 H1 |& r2 i: ?) X
to gonadotropin and to topical testosterone independently.! t& S+ D' @/ Z2 R& c$ W8 G
MATERIALS AND METHODS5 c' h/ O# a4 _+ V
Five 46 XY male subjects between 3 and 17 years old were
$ O$ Z* y' Q6 eevaluated for serum testosterone levels and hypothalamic$ [, @5 A( g5 ^5 j" Q/ K, L
function. Of these 5 boys 2 were considered to have Kallmann's
# |7 l& F) V' Msyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' Y: E' Q% P, A$ {! z/ ^lamic deficiency. After evaluation of response to luteinizing
- w) p4 I6 y5 {! ?7 ]" N! b& {hormone-releasing hormone these patients were treated with9 W7 B3 W3 s" w9 A# }
1,000 units of gonadotropin weekly for 3 weeks. Six weeks' L3 v' N! D5 C" o5 [
after completion of gonadotropin therapy 10 per cent topical2 L& E+ \2 \ g, y/ Z1 \+ ]
testosterone was applied to the phallus twice daily for 3 weeks.
5 f) V5 p. R* v2 p! r5 W ]' DSerum testosterone, luteinizing hormone and follicle-stimulat-
& R3 Z( x5 A3 n& v; ting hormone were monitored before, during and after comple-% e& L( t. |9 y0 F% F
tion of each phase of therapy. Penile stretch length was
) e) s1 l' L' qobtained by measuring from the symphysis pubis to the tip of
k i# y j% G1 ]3 U4 J- b/ I5 n/ ythe glans. Penile circumferential (girth) measurements were
- p; I8 T+ V" W7 w* uobtained using an orthopedic digital measuring device (see! r9 k1 `% J9 n' l) T
figure).
5 O1 {0 i$ Y+ C3 W1 E" X# cRESULTS
( x" z+ f, N0 u% ]- K- iSerum testosterone increased moderately to levels between
5 P, r- ` N4 Y# f. B5 @' L50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
: G# E0 x+ \% Kterone levels with topical testosterone remained near pre-
; C, u1 t. f. F$ G1 Atreatment levels (35 ng./dl.) or were elevated to similar levels, A" h1 t! a2 K' H7 l/ [4 U
developed after gonadotropin therapy (96 ng./dl.). Higher3 ]% c3 T; [- {* h l4 z
serum levels were noted in older patients (12 and 17 years old),
' Q8 B- R3 a" C) X5 Z# }while lower levels persisted in younger patients (4, 8, and 10
! u& `+ N8 n8 Q5 u; o5 pyears old) (see table). Despite absence of profound alterations6 o& t* E. m& O* x3 S" J2 w* z
of serum testosterone the topical therapy provided a greater: G* c$ f$ j/ u. D& T: \
Accepted for publication July 1, 1977. ·$ b; i1 x* k4 k3 _: X% I! P$ _# I
Read at annual meeting of American Urological Association,
# ~% Z0 X7 P( tChicago, Illinois, April 24-28, 1977.; K }; ^0 ]: q. S" B
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 a; o8 O7 V# e ?2799 W. Grand Blvd., Detroit, Michigan 48202.
/ I- {2 o3 Z: O, ximprovement in phallic growth compared to gonadotropin.9 ^1 u+ W0 p; Q+ t
Average phallic growth with gonadotropin was 14.3 per cent
8 g* s' T+ u, o: J+ V! c* aincrease in length and 5.0 per cent increase of girth. Topical: c+ g# @: y6 C, J) m2 l
testosterone produced a 60.0 per cent increase of phallic length) W7 Y! W! D& |0 n; q
and 52.9 per cent increase of girth (circumference). The' r& ]: Y) i8 {) k1 H
response to topical testosterone was greatest in children be-
* p2 k) W) Y d2 Etween 4 and 8 years old, with a gradual decrease to age 17. }$ a/ [3 S' C# E+ o
years (see table).. i C" ? l2 A' `2 k9 R2 E
DISCUSSION7 \! P7 K9 S$ Y7 ]
Topical testosterone has been used effectively by other
+ D7 q3 Y* Y3 r: h- M) @clinicians but its mode of action remains controversial. Im-
( @/ ^) K! g2 n* j- A, Y7 Hmergut and associates reported an excellent growth response
9 l" S) h `( F7 T; v7 x' vto topical testosterone with low levels of serum testosterone,
0 ?4 F7 Z2 S) J q+ }' Tsuggesting a local effect.1 Others have obtained growth re-7 {6 M- ]5 z$ h; I( u7 _5 s: F L
sponse with high. levels of serum testosterone after topical
$ o% m9 K4 Y! a9 Y4 Madministration, suggesting a systemic response. 3 The use of
% p: N3 I$ ?: J5 v1 X% n& Cgonadotropin to obtain levels of serum testosterone compara-/ H, S$ a. }. [
ble to levels obtained with topical testosterone would seem to
/ a7 h; t8 k: f8 \/ u Bprovide a means to compare the relative effectiveness of* f2 {7 J7 ~8 `2 y3 J$ p- M
topical testosterone to systemic testosterone effect. It cer-
! L' ]4 I( {& qtainly has been established that gonadotropin as well as par-- s0 w2 Z. L3 L+ s8 y0 \* P
enteral testosterone administration will produce genital1 X c( n8 ~$ c
growth. Our report shows that the growth of the phallus was8 q5 o( u2 i3 M9 _, ~9 [$ z
significantly greater with topical applications than with go-
2 s4 e+ {" q1 inadotropin, particularly in children less than 10 years old.
+ E6 A. N' F2 @9 n& UThe levels of serum testosterone remained similar or lower
7 j0 O% Y, c7 Fthan with gonadotropin during therapy, suggesting that topi-
, Y# e Q* s3 G# l& gcal application produces genital growth by its local effect as h( K6 k' {( i# }
well as its systemic effect.
0 R/ g! n, v# b8 t$ J6 F, nReview of our patients and their growth response related to
$ x6 t {4 `. k! ]& Xage shows a greater growth response at an earlier age. This is
1 v7 q# R, I* T2 I2 y( Gconsistent with the findings of Wilson and Walker, who
8 F' C" w. [/ L& y/ sreported an increased conversion of testosterone to dihydrotes-
& D' C) `2 D; m C! e+ K2 ~tosterone in the foreskin of neonates and infants.4 This activ-
2 C( Y, p; X$ u$ [1 G3 g& R" Iity gradually decreases with age until puberty when it ap-
$ |/ J# L* h' B$ {proaches the same level of activity as peripheral skin. It may
1 }7 t1 t L' _: n! o. pwell be that absorption of testosterone is less when applied at
2 ^( v! `7 T+ pan earlier age as suggested by lower serum levels in children
5 Z; |: i1 `3 k' Zless than 10 years old. This fact may be explained by the- w2 {/ T9 \# ~6 x) t; }3 y. j
greater ability of phallic skin to convert testosterone to dihy-6 {! I$ s! M, `$ J4 Y# m$ K
drotestosterone at this age. Conversely, serum levels in older) w8 J4 [* x( n0 I+ P
patients were higher, possibly because of decreased local0 T3 ]6 F! v) ^4 ?0 F( w
667) t$ m6 ^( G1 x0 x" n9 w! k, m
668 KLUGO AND CERNY* y+ i8 |8 `* R
Pt. Age, S0 m# T, m# I3 M
(yrs.)
8 e9 M+ Y( D: O7 f$ ?* {Serum Testosterone Phallus (cm.) Change Length
* E" k& ` ?, w% l& C y: ](ng./dl.) Girth x Length (%)
: P+ m8 K0 g$ M8 r% e41 ^& h0 W9 Z' |- ^) c" v
8
; n! ~5 ]$ ? a$ o' e* a Q10# j9 h; }2 v$ j. ]8 [$ C; {
12
3 O( Z- U5 i. {17
W3 I, k; l4 N: O R" cGonadotropin
! r# a: w- ~' ?) Q, E71.6 2.0 X 3 16.6. t( j5 t( U$ r: ^
50.4 4.0 X 5.0 20.0
3 v( k7 ^ f( ?, |22.0 4.5 X 4.0 25.0
( ^: z0 z' ^4 u1 } F( n6 {& ^! d84.6 4.0 X 4.5 11.1" L5 S: n, Z8 S ^
85.9 4.5 X 5.5 9.0
! {6 B! w* |: B: _. RAv. 14.3
8 l5 G0 o4 A% [6 @4; {* L _3 v- k: N( c) V8 h
8
2 n! f5 {5 F1 O5 m4 `) {10: |+ s: f+ u9 x$ j5 j6 @
12
# ~3 r# ]/ Z: S17
/ r6 o" j- k r' nTopical testosterone& C* k' `- N4 a! r8 }5 n
34.6 4.5 X 6.5 85
& I" q" f- ]7 Q |% o/ H38.8 6.0 X 8.5 707 w& t: S& Z; d4 l8 Y4 ?" J! i# l8 E
40.0 6.0 X 6.5 62.56 ~4 S/ F7 z0 m, h6 c* }$ _5 M
93.6 6.0 X 7.0 55.58 w- S, W9 f& @9 f( \9 U6 G0 k
95.0 6.5 X 7.0 27.2/ E0 l, G7 g" ?' i( r) C$ D
Av. 60.0
, P$ a. h b4 S; a! l$ i' ^ Havailable testosterone. Again, emphasis should be placed on
" W* Q( _% L9 mearly therapy when lower levels of testosterone appear to' i; X9 Q! ^8 V: B: G+ z( K
provide the best responses. The earlier therapy is instituted I# o0 P. G, o l- x4 a: w
the more likely there will be an excellent response with low
8 z; n* U" b( n; X9 nserum levels. Response occurs throughout adolescence as0 W! C' M7 _. F. D3 L
noted in nomograms of phallic growth. 7 The actual response1 |; n" g: K& r
to a given serum level of testosterone is much greater at birth
5 L$ V/ _0 O2 U% Tand gradually decreases as boys reach puberty. This is most' C3 b$ y$ o# \+ ]- j1 ]
likely related to the conversion of testosterone to dihydrotes-
( V0 x6 F- A: Z+ Z+ Rtosterone and correlates well with the studies of testosterone
6 N5 L! E2 z& ]; o$ U4 ]. s+ Yconversion in foreskin at various ages.1 d+ m; s+ H% u* \/ P
The question arises regarding early treatment as to whether
, |2 D4 R$ M% _# gone might sacrifice ultimate potential growth as with acceler-
5 N- b7 H! _2 Z# w' t8 `ated bone growth. The situation appears quite the reverse" F% k& E7 z, S( R0 D4 h, Y
with phallic response. If the early growth period is not used
% |( X) i# ^& Rwhen 5a reductase activity is greatest then potential growth
0 _% Y8 G! }; u6 ]may be lost. We have not observed any regression of growth
. `) C1 h4 p" A# \& wattained with topical or gonadotropin therapy. It may well
# D- L& O6 H* xbe that some patients will show little or no response to any
) |$ W4 N. p# e4 p& |; |# Gform of therapy. This would suggest a defect in the ability to6 k$ \% A6 ~: I
convert testosterone to dihydrotestosterone and indicate that
6 D# x7 I/ E8 A0 R) g2 h- Q. tphallic and peripheral skin, and subcutaneous tissue should! G5 {5 p9 |' K# [' h+ f* \8 C
be compared for 5a reductase activity.9 X% I# c( u( u0 C
A, loop enlarges to measure penile girth in millimeters. B,8 R$ `7 x! Q1 W) L a9 u) @1 I
example of penile girth computed easily and accurately.- M. C. B# k4 y7 i7 N
conversion of testosterone to dihydrotestosterone. It is in this
) N, l, z# Y4 v5 G& xolder group that others have noted high levels of serum
) G; f& a' O/ V; |testosterone with topical application. It would also appear& k% J, a4 S, A5 O+ g& ^) w
that phallic response during puberty is related directly to the; h( q2 r* d( Y. ~7 A1 U
serum testosterone level. There also is other evidence of local
) D* m% h% c: b1 z2 J# N3 ^7 `response to testosterone with hair growth and with spermato-9 b0 Z" }/ t( U9 m( c; p
genesis. 5• 6
0 f h" Y- ]8 f/ M; qAdministration of larger doses of gonadotropin or systemic, `9 A# E* u- R' _" j! @# V
testosterone, as well as topical applications that produce7 ]7 H) E9 r( S
higher levels of serum testosterone (150 to 900 ng./dl.), will
/ ~" M+ H; [( h/ J/ q! S7 }also produce phallic growth but risks accelerated skeletal: N$ s$ m: }) Q0 A. W9 R9 B
maturation even after stopping treatment. It would appear
3 S+ c) b! u# L- C8 p! ?+ y. qthat this may be avoided by topical applications of testosterone y; M7 [" Y& a W, R
and monitoring of serum testosterone. Even with this control
, d" i$ ~( w0 N: Wthe duration of our therapy did not exceed 3 weeks at any; Q3 d1 X5 O% y/ \: y( n6 k
time. It is apparent that the prepuberal male subject may2 y. m% J; P" N# I; s4 M
suffer accelerated bone growth with testosterone levels near
( ^8 _& q; _. j" E$ @+ C200 ng./dl. When skeletal maturation is complete the level of
3 X, x4 E) S& E8 P( yserum testosterone can be maintained in the 700 to 1,300 ng./2 ~# g! a- s! f1 ^
dl. range to stimulate phallic growth and secondary sexual
& B/ J# t* r) J* F1 A& Nchanges. Therefore, after skeletal maturation parenteral tes-
4 B5 T- r% a+ c. Y4 ktosterone may be used to advantage. Before skeletal matura-
, o& \, @: q5 i8 n: Mtion care must be taken to avoid maintaining levels of serum( l# I3 P) [' t5 s$ F2 y+ c# v
testosterone more than 100 ng./dl. Low-dose gonadotropin0 Q* c7 z# i9 f. M" b& w/ ?
depends upon intrinsic testicular activity and may require
$ o- E. m8 g, o3 A7 nprolonged administration for any response., d* z( X7 H4 u- t, Y0 `
Alternately, topical testosterone does not depend upon tes-- @! g9 I" `4 F& T7 N
ticular function and may provide a more constant level of
% U6 U. x# @' a& q! c2 s& UREFERENCES
2 l+ l) H( k! h. \, ]+ V1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# ]. f2 I/ [* [# [+ Y
R.: The local application of testosterone cream to the prepub-; r% V& j% P8 S1 f4 i
ertal phallus. J. Urol., 105: 905, 1971.) Y' ]+ L1 N0 L0 ^! z( U g
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
: [" \) a) z! L4 n$ S ltreatment for micropenis during early childhood. J. Pediat.,! p0 P+ [; X2 _9 J+ r& C+ g
83: 247, 1973.8 K2 P: \3 U) a3 `
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; t. c0 R! y: o) P
one therapy for penile growth. Urology, 6: 708, 1975.9 p0 N5 j- I# ~4 L$ O. d
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 e# h* l3 Q# {! q/ ?1 sto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by; g7 [: \# W" G" h q
skin slices of man. J. Clin. Invest., 48: 371, 1969.% b3 @8 D/ n0 h5 d, k9 E$ r
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
! s: J$ C6 N9 y7 n9 i* e9 M. S0 ]' Rby topical application of androgens. J.A.M.A., 191: 521, 1965." [5 S" ~+ B8 |5 s
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ v/ v3 T8 L# @# C& ~( Q+ ?# tandrogenic effect of interstitial cell tumor of the testis. J.& G4 o& W/ _; a% e
Urol., 104: 774, 1970.( i) K5 U% F H$ P
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 b+ }3 d, _* @
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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