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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
# u0 t# a, v; uGONADOTROPIN4 j- ^3 {4 W8 x# q# @8 b4 u  Z  Q
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. z3 T: p# B+ n0 Z$ JFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 h1 Q. I0 S' Z3 b6 p6 ^
ABSTRACT
) j5 O& c: ]; x7 W+ r9 b5 L' JFive patients were treated with gonadotropin and topical testosterone for micropenis associated0 i  G9 @; _6 a  k' W! g! O* J
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
- ^" Q/ K( m8 A  a9 btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
1 c+ x" ]. N- H2 acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent4 j1 v$ J; E$ X6 I  X8 f" g0 _( \
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
" m0 Q6 H9 X/ I+ {: ~increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 W1 p: E; c8 e) |8 L& Iincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" ?$ L! a, M6 @( m* a4 Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
9 _2 i' x1 I: @7 G1 [- x9 d& Qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile1 f* Z3 ?5 D* {, g4 F& F
growth. The response appears to be greater in younger children, which is consistent with previ-# _% [$ {, D  s3 f
ously published studies of age-related 5 reductase activity.- @' L$ \5 ]' p' w& z+ y
Children with microphallus regardless of its etiology will
4 }1 L; s, I$ w( r/ U5 f0 grequire augmentation or consideration for alteration of exter-
+ E" @, i( u- inal genitalia. In many instances urethroplasty for hypo-2 L) K( H) S( M6 O( {& P
spadias is easier with previous stimulation of phallic growth.# A% a# k# M( g& z- s  ?8 T6 f) `
The use of testosterone administered parenterally or topically3 I9 c2 Z$ W! a& @4 H
has produced effective phallic growth. 1- 3 The mechanism of
5 b( T* L- ~, z( j& vresponse has been considered as local or systemic. With this, k+ r6 d) y9 u7 Y! F* o! x1 d4 I
in mind we studied 5 children with microphallus for response/ c4 H9 g+ c, R$ d) o3 [' ]. C( R
to gonadotropin and to topical testosterone independently.- M8 \2 n) m& V4 f! ?" j
MATERIALS AND METHODS- s; f" G, d5 P. g' r* H' I
Five 46 XY male subjects between 3 and 17 years old were
- [/ r2 J6 `7 A3 Y4 y5 q4 Sevaluated for serum testosterone levels and hypothalamic
; p) v9 l+ j7 Q: o. Pfunction. Of these 5 boys 2 were considered to have Kallmann's
* M( Y/ R) f- k; h6 [2 csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
$ G! q3 f) W  B# q  s7 }lamic deficiency. After evaluation of response to luteinizing( Q2 o- Z! W( t, `2 N
hormone-releasing hormone these patients were treated with3 ^" F' W/ k. h* _" p! U  K' {
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% A% T% f/ P+ {0 X/ P$ ^# Fafter completion of gonadotropin therapy 10 per cent topical; z9 k$ G  \, G3 W. f" _4 q
testosterone was applied to the phallus twice daily for 3 weeks.
" G" Q  e9 M: Z' z1 d2 zSerum testosterone, luteinizing hormone and follicle-stimulat-
; G, p- ^9 C8 d4 ~3 c+ n/ bing hormone were monitored before, during and after comple-& P9 U  l, Z! W* O" Q
tion of each phase of therapy. Penile stretch length was/ D6 U/ O6 T) c4 x7 Y' h
obtained by measuring from the symphysis pubis to the tip of8 f8 y8 k9 P; y+ @& t
the glans. Penile circumferential (girth) measurements were1 |, W0 g, @( O: Y& a+ z( ~- `
obtained using an orthopedic digital measuring device (see
5 e4 C8 J8 G0 K4 lfigure).
: D/ v6 l  k# e$ L3 l9 lRESULTS
; Z) u. s, p- b- {8 Z$ {Serum testosterone increased moderately to levels between" J% H9 U% G3 k$ c% {! s
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) d  _1 q) N" |, J. B+ H, t* o' Fterone levels with topical testosterone remained near pre-
9 ^# H9 l( {( I% Jtreatment levels (35 ng./dl.) or were elevated to similar levels
7 H) @/ R- k- L' z  I& e1 G% adeveloped after gonadotropin therapy (96 ng./dl.). Higher2 d' }% f. Y- M. K- g( F1 e: i
serum levels were noted in older patients (12 and 17 years old),
/ {0 `( f& L; e' H+ M  ?while lower levels persisted in younger patients (4, 8, and 107 D1 r- g2 \" n5 S% X
years old) (see table). Despite absence of profound alterations3 B& z, O6 M5 z$ x
of serum testosterone the topical therapy provided a greater: z/ }/ g9 C5 S
Accepted for publication July 1, 1977. ·
; u# t1 D# I* y, W; P( e7 t& WRead at annual meeting of American Urological Association,
' F) N" K* r! aChicago, Illinois, April 24-28, 1977./ `7 y& g9 t5 V* I! e* x6 T
* Requests for reprints: Division of Urology, Henry Ford Hospital,
$ G* \3 N/ M' o" q2 H; p2799 W. Grand Blvd., Detroit, Michigan 48202.9 W4 g1 k* T7 Q1 h0 e9 T5 U
improvement in phallic growth compared to gonadotropin.& Q: E+ K  I  l5 v" T8 H) h
Average phallic growth with gonadotropin was 14.3 per cent
. m4 T# ?! v$ N0 z9 M# yincrease in length and 5.0 per cent increase of girth. Topical( c( C6 m/ C% D
testosterone produced a 60.0 per cent increase of phallic length
3 y' Y, Y" _0 O7 \2 x! A: X1 t. Vand 52.9 per cent increase of girth (circumference). The
, c3 ~+ z7 J9 l% u% C. b* o5 l1 hresponse to topical testosterone was greatest in children be-( n  @# \* G% [) `
tween 4 and 8 years old, with a gradual decrease to age 17# {) Y/ [8 F& I/ _6 N
years (see table).
& ~: a0 g# \& I8 y) S/ o% RDISCUSSION
, C6 K  y9 v7 S9 l; v/ F  {Topical testosterone has been used effectively by other
9 a( q( B' B& O. D( F$ u/ c- f( w7 b3 j3 yclinicians but its mode of action remains controversial. Im-
$ G0 d! U- x! Amergut and associates reported an excellent growth response
: A" Q; M; q2 ^9 e8 ito topical testosterone with low levels of serum testosterone,& Q$ T( ^) x  b& B" p/ H( |4 _% O
suggesting a local effect.1 Others have obtained growth re-
" @: P+ k2 o9 f/ Z( ~sponse with high. levels of serum testosterone after topical  I9 d; W/ F# V' V6 P+ U  q
administration, suggesting a systemic response. 3 The use of
$ C$ m( p+ W& P$ _, m% I/ N/ P# hgonadotropin to obtain levels of serum testosterone compara-
  C9 t# ?; e/ z& V$ @ble to levels obtained with topical testosterone would seem to  ~/ H" P3 B) I! B: B6 c
provide a means to compare the relative effectiveness of7 e2 t0 f- }0 S
topical testosterone to systemic testosterone effect. It cer-
8 \# V3 T$ y2 _: _tainly has been established that gonadotropin as well as par-
* ^# ?4 \6 m1 \enteral testosterone administration will produce genital
  E: W/ a7 f: S1 M5 p! N5 R8 Tgrowth. Our report shows that the growth of the phallus was& w$ A: v; G. q- c
significantly greater with topical applications than with go-* d0 e9 C9 |5 E# [
nadotropin, particularly in children less than 10 years old./ R4 k* I( C2 M* P8 T
The levels of serum testosterone remained similar or lower
0 g* s& C. s( b4 s7 T+ ~/ \than with gonadotropin during therapy, suggesting that topi-5 ?( ]9 G# `& j8 W4 P* T$ B
cal application produces genital growth by its local effect as) S, y# e* X0 J8 @- l2 b1 U/ ^# ]: t
well as its systemic effect.- e/ v" d  b- C  S0 |
Review of our patients and their growth response related to5 R, R: \7 n, L! e5 v
age shows a greater growth response at an earlier age. This is; U; d6 O- @& D
consistent with the findings of Wilson and Walker, who
8 V4 \9 z0 o/ S$ |$ Greported an increased conversion of testosterone to dihydrotes-# z  O0 `4 j8 K( ~3 o
tosterone in the foreskin of neonates and infants.4 This activ-
/ A( R! |5 [7 [4 Hity gradually decreases with age until puberty when it ap-
8 w1 T6 W" a( s- Mproaches the same level of activity as peripheral skin. It may
" w, Z0 H! h) f; b/ Z- C( Ywell be that absorption of testosterone is less when applied at* t7 I2 J# Q" ]
an earlier age as suggested by lower serum levels in children4 F( Y& l" O: J* i* r
less than 10 years old. This fact may be explained by the
. o9 \* B  Q$ O# i8 e: Z7 zgreater ability of phallic skin to convert testosterone to dihy-% b3 ^5 h' h: X( I! H) Z! f5 `+ S* P
drotestosterone at this age. Conversely, serum levels in older0 a4 `7 d& {: f
patients were higher, possibly because of decreased local  @- j4 y/ y* C8 F; X
667* b2 }9 _, I# N/ u7 q
668 KLUGO AND CERNY
0 R/ Z8 J+ ^7 ?Pt. Age
' F6 E2 z2 m. l' @: J. M(yrs.)9 ~0 X% V  G$ u9 i8 [* v+ j
Serum Testosterone Phallus (cm.) Change Length
" A% A  t5 O4 w! K(ng./dl.) Girth x Length (%)
2 {) j% j* o; U- v42 H: W/ I7 x* r" e
8
7 M* K& I8 |8 \& v  G; R5 V5 [10
/ a" n! ?* G$ B$ `. x* b12
  C( o, Y  q( r4 R, j- L8 O9 P177 O1 V& k; v( K  x6 N1 r
Gonadotropin& h" E0 v' r+ y
71.6 2.0 X 3 16.6% d* w2 Q: ], |( g5 N7 H: `
50.4 4.0 X 5.0 20.04 A6 n! I$ @; t
22.0 4.5 X 4.0 25.0
' x$ X' J4 Z3 ~: z) z. C( F% D* S84.6 4.0 X 4.5 11.1+ Z$ e) A' ~* {$ W( E
85.9 4.5 X 5.5 9.05 ]% s5 h* w& q1 i- O* N
Av. 14.3$ y% O1 P! E, C: V& n& F
4
5 r5 k$ @% Q2 \- q8* y3 r. W0 |2 ~% l% R" b" f  ~
10
' I2 T$ D+ p& L. O$ |1 d8 v12
9 O) Q3 R( c: D- ]- I17* R/ f2 L9 U# \$ u
Topical testosterone4 A% y2 r: v% P9 M
34.6 4.5 X 6.5 85) F- T' L9 f+ S  E
38.8 6.0 X 8.5 70
) g4 L& r" [  }5 R40.0 6.0 X 6.5 62.5: D1 `; `. e4 z: l
93.6 6.0 X 7.0 55.5$ ?; v8 L! q& r: U
95.0 6.5 X 7.0 27.2
: T; F/ Y4 u6 J3 |1 u: CAv. 60.0% X* F! e& R; c& D" `; I
available testosterone. Again, emphasis should be placed on4 p2 s  U- s8 p. a( k" V
early therapy when lower levels of testosterone appear to
! [% c7 c+ ]! hprovide the best responses. The earlier therapy is instituted* J, ?! g! l. M. b
the more likely there will be an excellent response with low1 u+ p1 o5 {* z4 X2 c
serum levels. Response occurs throughout adolescence as" l8 O( D5 G& z* j" G% i, Y4 w
noted in nomograms of phallic growth. 7 The actual response
: W. j2 H: Q* U) a5 I4 bto a given serum level of testosterone is much greater at birth: Z0 E6 Y& G! i5 s
and gradually decreases as boys reach puberty. This is most; O- Q# h+ h. y$ Y: |
likely related to the conversion of testosterone to dihydrotes-
3 k: i. c& y  S  `$ R+ k, G- etosterone and correlates well with the studies of testosterone
: m7 [4 N: v; aconversion in foreskin at various ages.1 U7 z" J# U' F/ e4 I
The question arises regarding early treatment as to whether
6 U; U% y' m* O9 L% J. k( Eone might sacrifice ultimate potential growth as with acceler-
1 m7 y3 F( n9 z4 v2 q1 oated bone growth. The situation appears quite the reverse
) W. b$ t! {# q( ?$ f" vwith phallic response. If the early growth period is not used2 P. F. }6 {7 K  o/ k+ J/ [1 R
when 5a reductase activity is greatest then potential growth
8 f# q! |  z( r8 ]may be lost. We have not observed any regression of growth
% s+ @& d! N& J/ ^3 i2 z2 Cattained with topical or gonadotropin therapy. It may well, @6 I0 T. @1 m& C9 B
be that some patients will show little or no response to any* k& z* O1 B) h) ]
form of therapy. This would suggest a defect in the ability to, w( t1 c  V8 f" I/ u: P
convert testosterone to dihydrotestosterone and indicate that
8 u' ]# u; ?% I1 Y$ B8 Qphallic and peripheral skin, and subcutaneous tissue should1 g0 U$ ]/ n% L+ m* F. T- y
be compared for 5a reductase activity.( n) V2 }) o1 J* V) R
A, loop enlarges to measure penile girth in millimeters. B,# _  ?. j. W! n6 j
example of penile girth computed easily and accurately.1 H9 `# j/ E* M& T
conversion of testosterone to dihydrotestosterone. It is in this8 l( {& y+ D; v0 {$ o
older group that others have noted high levels of serum
' Z6 k7 n/ X# ^0 E' ftestosterone with topical application. It would also appear
3 d6 m, K$ y. S' nthat phallic response during puberty is related directly to the3 S3 Y% g0 c8 G* C& a
serum testosterone level. There also is other evidence of local' x9 x! I, r/ w+ R2 g' T0 K
response to testosterone with hair growth and with spermato-. b* b# V$ P- t
genesis. 5• 6
- x7 ~) `, n" r( v: \2 qAdministration of larger doses of gonadotropin or systemic- |# I. o3 G: }1 t0 ?
testosterone, as well as topical applications that produce5 M# `8 u4 q7 n4 ^- q. O
higher levels of serum testosterone (150 to 900 ng./dl.), will
8 j' g( u: B9 D0 _6 F, calso produce phallic growth but risks accelerated skeletal" ?% O- W' ^, z3 J. J- J, V$ |2 u/ R
maturation even after stopping treatment. It would appear% I% s* B0 _8 N, ~* }1 J6 {
that this may be avoided by topical applications of testosterone& F& T1 J" S  l; V8 @9 q
and monitoring of serum testosterone. Even with this control
- {: ?5 F! Y/ D5 H  }; ^7 R$ o0 {, fthe duration of our therapy did not exceed 3 weeks at any
' h0 A/ m9 r+ ktime. It is apparent that the prepuberal male subject may3 g  N* X0 \# S5 K' _, M7 t1 ?9 t
suffer accelerated bone growth with testosterone levels near+ X. l9 \9 j% B+ I
200 ng./dl. When skeletal maturation is complete the level of
1 F; a) Y9 z1 O8 K6 fserum testosterone can be maintained in the 700 to 1,300 ng./$ m3 H1 J$ l& ?
dl. range to stimulate phallic growth and secondary sexual
9 Q  U8 T* h' G7 t' F: Y: Pchanges. Therefore, after skeletal maturation parenteral tes-
, w8 p  k, Y: a& U: L! z) Htosterone may be used to advantage. Before skeletal matura-. _8 I6 E0 I0 d/ b! h* G
tion care must be taken to avoid maintaining levels of serum
3 c; }, T, a4 t6 \testosterone more than 100 ng./dl. Low-dose gonadotropin
; W8 |' |7 p  b- f1 Ddepends upon intrinsic testicular activity and may require8 Y2 y% }, F( j6 C2 g- U' _. K
prolonged administration for any response.
2 K; e8 `, D8 W) l9 b3 B- Q$ q* l) ]Alternately, topical testosterone does not depend upon tes-# x9 U- {/ R" m5 \4 R" m8 b2 @' t
ticular function and may provide a more constant level of6 f1 h5 f4 G2 ^" X, \
REFERENCES$ l" d3 [, [9 b% a2 `) R& d
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( B2 P- W) X/ v0 {& W
R.: The local application of testosterone cream to the prepub-( ^- J/ j/ {0 \) t2 L
ertal phallus. J. Urol., 105: 905, 1971.* ?9 Y! }5 I2 O
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 v- _4 T& k. m+ Y( u2 p6 R
treatment for micropenis during early childhood. J. Pediat.,7 p* M; c! d1 K
83: 247, 1973.
' L* z" J& |4 [1 m9 V: P) _8 j" G3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, K( U1 t+ e' U+ u" n2 \+ p5 sone therapy for penile growth. Urology, 6: 708, 1975.: S# L" G- L/ J& h# ], K9 p
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 u. c4 V  d4 L: h" gto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 w& t6 }% E; R5 n" a% y* B/ c
skin slices of man. J. Clin. Invest., 48: 371, 1969." s( F0 o, _* @8 s
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ v* f, J& e8 ~+ ~; P& Iby topical application of androgens. J.A.M.A., 191: 521, 1965.
: T6 N' {. W' i6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 k  {$ u) T" k" X% @# V% n3 Iandrogenic effect of interstitial cell tumor of the testis. J.
6 v% p  K# B% v2 oUrol., 104: 774, 1970.
% t' ^( |# F& j" f! l$ A7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
  U7 q! Z1 g$ S3 y1 ~' k# Mtion in the male genitalia from birth to maturity. J. Urol., 48:
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