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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
/ [$ D' Z4 }* v6 _8 L! D$ z8 uGONADOTROPIN7 j& X% k: Q7 ~4 Q/ O
RICHARD C. KLUGO* AND JOSEPH C. CERNY% R( P# E: [' ]! s9 r
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' ^" s4 t: K, F
ABSTRACT
, X- [: Q* R' l4 W$ O7 h# `1 q8 AFive patients were treated with gonadotropin and topical testosterone for micropenis associated, v% x: A& N+ u7 k, f: t
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. M- j: _1 L% l9 Q* n
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 [# {$ [% k/ ?+ D" K7 kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 Y9 @/ b; w& s9 Wfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 i4 t7 g' Y. \! C7 l) ^) P. O. L
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average2 C( _3 c6 b+ A
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ W+ f# B3 d3 L3 x( _
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This* V0 W4 Q  l) c5 G+ u
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- }, x# i1 ~# s; H. k8 \4 Tgrowth. The response appears to be greater in younger children, which is consistent with previ-
6 C; V2 w5 Q  @4 u! P. Jously published studies of age-related 5 reductase activity.: p% E* s) {) t& y, L* ?2 G  x, E
Children with microphallus regardless of its etiology will" i6 ^5 ]% k6 [4 k
require augmentation or consideration for alteration of exter-
( P, ?1 N9 Y2 n) `6 v# Enal genitalia. In many instances urethroplasty for hypo-# E# w: \0 ~5 C/ I% V2 T
spadias is easier with previous stimulation of phallic growth.: f! b% e  z) R( _7 r& _1 ]) E
The use of testosterone administered parenterally or topically
" O& P# |$ [, y$ ^7 ]0 Xhas produced effective phallic growth. 1- 3 The mechanism of5 h# e% d5 F- ^5 R6 U2 C( `+ P4 O
response has been considered as local or systemic. With this, _# K: b( E1 ?' M$ ?
in mind we studied 5 children with microphallus for response
/ M+ b' g+ ?7 _- O9 ^- Wto gonadotropin and to topical testosterone independently.- p+ u! N9 a1 O2 p! l+ w' U
MATERIALS AND METHODS) w" T; A" j8 S, i& g
Five 46 XY male subjects between 3 and 17 years old were
; E" A; O0 W' Z, L. Z7 pevaluated for serum testosterone levels and hypothalamic, i" z' T' O- B) S( S/ I: F
function. Of these 5 boys 2 were considered to have Kallmann's3 g/ N9 j% T5 e
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) q6 n5 b  [! `$ @8 g' w5 ~lamic deficiency. After evaluation of response to luteinizing" Y$ l+ K( x& w- y7 C" W) W6 ~) C' P3 z/ X
hormone-releasing hormone these patients were treated with0 u8 f" j0 ~3 u
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
: F7 k$ u! h9 Wafter completion of gonadotropin therapy 10 per cent topical
) {& \+ l' f6 @6 t6 s# Rtestosterone was applied to the phallus twice daily for 3 weeks.. E& I- J) q2 N; J
Serum testosterone, luteinizing hormone and follicle-stimulat-
( D$ s9 C( q9 J; u  Y, i9 [ing hormone were monitored before, during and after comple-, U2 i5 u  Y# F) j
tion of each phase of therapy. Penile stretch length was
/ a- V1 i. o% B6 `obtained by measuring from the symphysis pubis to the tip of
2 n( e* [. k9 Z; o* g& }2 A& m% Fthe glans. Penile circumferential (girth) measurements were% Y* v3 j9 i3 ]. \, p2 Z4 F
obtained using an orthopedic digital measuring device (see% v# y. g( B4 M8 m# U/ Z$ D5 n$ i
figure).
: U7 J( s2 }* v/ `6 i6 n7 @6 dRESULTS
$ W1 B0 A" _$ f! L) nSerum testosterone increased moderately to levels between
' v2 Y; C1 }& u" V, o, M50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  [! m9 D5 |2 H- k# P0 H, K0 c( [terone levels with topical testosterone remained near pre-' D4 b9 Z9 N7 P/ M. l! b* K
treatment levels (35 ng./dl.) or were elevated to similar levels
# X& {8 o* A2 z  ~developed after gonadotropin therapy (96 ng./dl.). Higher, ]. z  U0 y: s, ^; P$ L8 l& B
serum levels were noted in older patients (12 and 17 years old),
" P* K* ]( J3 a, U3 H  swhile lower levels persisted in younger patients (4, 8, and 108 @  g1 N" {5 V) `
years old) (see table). Despite absence of profound alterations5 D2 }- Z: h. ~3 x
of serum testosterone the topical therapy provided a greater0 d# k. X, \3 l5 S) a
Accepted for publication July 1, 1977. ·% W  \! T& J2 H
Read at annual meeting of American Urological Association,* P+ S& b3 v, x* Q" J
Chicago, Illinois, April 24-28, 1977.1 C$ k+ J# [  N+ E
* Requests for reprints: Division of Urology, Henry Ford Hospital,. U* \2 K' N- V8 _. o* t- X
2799 W. Grand Blvd., Detroit, Michigan 48202.
) e4 [5 |0 ^) Rimprovement in phallic growth compared to gonadotropin.1 D  X# Y3 Q4 l0 e8 q) T
Average phallic growth with gonadotropin was 14.3 per cent1 k/ p8 B, T: R! A; u
increase in length and 5.0 per cent increase of girth. Topical
) F, y* V# G3 }3 Q2 _. }( Ftestosterone produced a 60.0 per cent increase of phallic length! A' R. ?4 K$ c5 L5 Z% d
and 52.9 per cent increase of girth (circumference). The
# Q1 V0 i6 N; L4 j  J) @6 W( y# ~9 Jresponse to topical testosterone was greatest in children be-
+ _( V9 m. K7 e- n4 F7 V* m4 C2 _tween 4 and 8 years old, with a gradual decrease to age 17
3 h" Z) b. T% Q. ?% V0 l9 yyears (see table).
" b+ q+ w' U7 N4 R0 D! EDISCUSSION% N. u2 ]8 t; `' S3 j2 X" h4 A
Topical testosterone has been used effectively by other
1 o2 v. U( H5 }3 Sclinicians but its mode of action remains controversial. Im-
  B7 Z; A5 v9 z+ g8 o) P+ S9 Gmergut and associates reported an excellent growth response
& B4 R) q4 F# ^. bto topical testosterone with low levels of serum testosterone,. W7 k6 n) k: l( a, F/ x# X. T- s
suggesting a local effect.1 Others have obtained growth re-% b/ j; o( I4 Y+ ^! T: u
sponse with high. levels of serum testosterone after topical
% i% z0 C- k2 y0 Y! ?8 A% b; Nadministration, suggesting a systemic response. 3 The use of# b$ K; X- D! o, h
gonadotropin to obtain levels of serum testosterone compara-' h9 y) b4 @4 M+ K4 {0 Q
ble to levels obtained with topical testosterone would seem to
. [/ ]% d  h3 `+ Xprovide a means to compare the relative effectiveness of
% U0 U% p2 V4 ~& ~* _topical testosterone to systemic testosterone effect. It cer-& ]! s0 t2 V$ k
tainly has been established that gonadotropin as well as par-. B, J( v* S* ?3 V% Y# K8 t
enteral testosterone administration will produce genital+ V9 j  v, E6 d% y% C) M7 ~9 M
growth. Our report shows that the growth of the phallus was+ r& }- ]# Z/ w6 Y7 d
significantly greater with topical applications than with go-0 f: r/ X. B) T* v1 D1 z
nadotropin, particularly in children less than 10 years old.  U9 H; d- P( ^, r4 ?+ j- Y
The levels of serum testosterone remained similar or lower
1 {: H# y8 ]0 P. }  t1 Y/ j$ Vthan with gonadotropin during therapy, suggesting that topi-
) U9 Y: m; l. G$ Ucal application produces genital growth by its local effect as0 {0 Q  z9 z) W
well as its systemic effect.& B/ m8 w; [, i( |, r" k! h
Review of our patients and their growth response related to
7 X1 h* A  N+ ?' Z7 X3 Q* f- jage shows a greater growth response at an earlier age. This is
5 A! L' U+ H( bconsistent with the findings of Wilson and Walker, who( d+ z+ o9 s8 G. p* [; ^
reported an increased conversion of testosterone to dihydrotes-& c/ Q* D, {/ T
tosterone in the foreskin of neonates and infants.4 This activ-
3 F. {  M( I# i/ ?  \* ^ity gradually decreases with age until puberty when it ap-
9 g0 _0 J9 }) F& Xproaches the same level of activity as peripheral skin. It may
- f+ Z* d- v: Vwell be that absorption of testosterone is less when applied at
6 a* {; j: D# _0 h$ h% A( Ian earlier age as suggested by lower serum levels in children+ S' L  Y0 G3 \9 Q) s% w) k5 P; k
less than 10 years old. This fact may be explained by the
! g3 ~2 W5 f" O6 wgreater ability of phallic skin to convert testosterone to dihy-3 w: Y7 T3 V4 f2 K
drotestosterone at this age. Conversely, serum levels in older% U4 a- l  H$ W% v
patients were higher, possibly because of decreased local) M( h. h5 y; g4 M. Z$ R8 ?1 D
667
& M( g* x# r; u! @) D) l" K4 t668 KLUGO AND CERNY
% K( e/ p8 o' P, c  y, bPt. Age* Y7 L; A6 `% d5 |" B5 O+ ~
(yrs.)
" D4 M: f$ K4 T7 U9 {Serum Testosterone Phallus (cm.) Change Length$ _0 d& Z/ O; I6 n/ H" ]
(ng./dl.) Girth x Length (%)! F. W* c1 e0 y/ _# a; R# R
4
, M2 L: W* U3 C% u, w) ]8
5 d$ u/ `  c& W2 `/ A: Q# m: `10% {5 N+ a: b3 G! a3 G
12
3 x7 Y5 f: @+ U: G9 O4 r, {* |% t0 k17
* u3 W( O) x2 r- n) F- i* v7 g$ O$ b5 aGonadotropin
1 U9 I; ?* ~2 m) w9 _71.6 2.0 X 3 16.6
. p7 D' n/ ?9 U7 o. z50.4 4.0 X 5.0 20.0
2 y/ s2 ^' q; V1 u9 A6 p22.0 4.5 X 4.0 25.0# V& c; y: D, u* o  X
84.6 4.0 X 4.5 11.1
7 v/ ]7 g7 Z  R8 o85.9 4.5 X 5.5 9.07 U/ W7 @, R6 t
Av. 14.3
# H9 Y" @: o$ J& T( I8 n" I4
1 n) Q! M7 V( l- R* i$ y87 c& o6 k/ e# e0 [. a
10: g. K" ]5 D% V5 t
124 r& Y( h! \9 k* d; Q0 G
17
) N; i. @# u7 E  g9 e6 E5 k: i; M7 uTopical testosterone9 D/ G1 [- H3 A2 K
34.6 4.5 X 6.5 85( j7 W" q7 P$ ^% @5 F
38.8 6.0 X 8.5 709 ^# {' L" N5 ~2 m% w4 R9 ?
40.0 6.0 X 6.5 62.5: o# B. w5 m" m( y0 P
93.6 6.0 X 7.0 55.5
1 g' U/ v& X0 K& W9 |3 M95.0 6.5 X 7.0 27.2
) k9 f3 w# ?7 b. [8 K4 E+ MAv. 60.0; z" l. D; }5 c
available testosterone. Again, emphasis should be placed on
: K" S; v; c0 q% Wearly therapy when lower levels of testosterone appear to+ J0 \( [: K) u  c& F' {
provide the best responses. The earlier therapy is instituted) ?' Z; A* s- P/ D
the more likely there will be an excellent response with low
% c: l7 T) G" F- T- P9 Eserum levels. Response occurs throughout adolescence as1 G, ]8 C# [* L' |+ L
noted in nomograms of phallic growth. 7 The actual response" N* A$ m: w; E9 \3 u4 c+ @
to a given serum level of testosterone is much greater at birth! t/ t$ h2 r0 ~: k& S+ a
and gradually decreases as boys reach puberty. This is most
1 o8 _/ E4 h6 n' j0 S7 Plikely related to the conversion of testosterone to dihydrotes-
( c; F' ?. f5 }; xtosterone and correlates well with the studies of testosterone
' L" C+ {- G: g: c. i! Jconversion in foreskin at various ages.1 F  h9 F' r; o0 T5 ~& z, a
The question arises regarding early treatment as to whether3 Y2 c. h6 _+ ?6 x/ o
one might sacrifice ultimate potential growth as with acceler-
  L! Q1 d! h1 Z( ~  g% ^4 Mated bone growth. The situation appears quite the reverse2 W2 C, A( c% O0 W+ k$ o
with phallic response. If the early growth period is not used
  C% Y0 ~/ u1 a( M2 J0 @- \; ywhen 5a reductase activity is greatest then potential growth
4 j: Y/ B# M$ ~6 `1 }6 L, H( vmay be lost. We have not observed any regression of growth
; C2 y6 G$ D! T/ Nattained with topical or gonadotropin therapy. It may well9 N  E, G9 c  e
be that some patients will show little or no response to any5 F: m( n' S; I
form of therapy. This would suggest a defect in the ability to+ u% |: M9 j  O" {8 j
convert testosterone to dihydrotestosterone and indicate that) W3 f; y4 ]# v$ ?
phallic and peripheral skin, and subcutaneous tissue should) H; ^+ c0 a# U. N* G
be compared for 5a reductase activity.
& J/ A0 _; v6 Y* M/ M0 [; ?A, loop enlarges to measure penile girth in millimeters. B,
2 Z9 u6 D% l! J& V8 yexample of penile girth computed easily and accurately.
1 C1 `- O" J6 }7 I7 Kconversion of testosterone to dihydrotestosterone. It is in this3 M; A& ?; f( m( ~) e3 @$ |
older group that others have noted high levels of serum
: `# F6 r" p' W" d0 Z3 T2 a' Atestosterone with topical application. It would also appear6 D0 E$ H9 l' S2 e$ `2 z
that phallic response during puberty is related directly to the
! U( i" K. V+ R& Hserum testosterone level. There also is other evidence of local. r7 }# v: Z- ^- H' L% h* D; S( n. F0 _
response to testosterone with hair growth and with spermato-: D& b/ ]* q% ?
genesis. 5• 69 M! [. n! f; {# M4 A' _: h
Administration of larger doses of gonadotropin or systemic2 p2 N8 K3 o9 ]% O* h
testosterone, as well as topical applications that produce% ~- Q$ X+ B9 p# f* ]
higher levels of serum testosterone (150 to 900 ng./dl.), will
, z9 L7 O$ [8 S% G1 qalso produce phallic growth but risks accelerated skeletal* e" ~+ j! c( f) W
maturation even after stopping treatment. It would appear
- s7 q# z8 g( L9 @that this may be avoided by topical applications of testosterone7 Q& V; N( U9 Z  h
and monitoring of serum testosterone. Even with this control
4 K# u( E# B$ {( T& N8 c8 M& Vthe duration of our therapy did not exceed 3 weeks at any
7 b' _. S4 Y1 k! Ftime. It is apparent that the prepuberal male subject may
' O4 o  e. J. D( {/ r  msuffer accelerated bone growth with testosterone levels near9 g, ?2 p( `4 J- X8 U2 Z- o+ X$ t7 Q" R
200 ng./dl. When skeletal maturation is complete the level of9 I: c0 a1 }8 x4 R
serum testosterone can be maintained in the 700 to 1,300 ng./
2 |* c0 ?0 ~. `3 N7 sdl. range to stimulate phallic growth and secondary sexual
$ \" k" z3 N; s/ ?# N$ E8 o! E/ Lchanges. Therefore, after skeletal maturation parenteral tes-3 }# x7 g/ R* r7 H: M. P  g
tosterone may be used to advantage. Before skeletal matura-! n; f- |8 I1 t; G0 P
tion care must be taken to avoid maintaining levels of serum
( d* {* n0 @3 Z. N4 X* c9 ^testosterone more than 100 ng./dl. Low-dose gonadotropin$ Q3 i- `' ~. x% Q& T9 E
depends upon intrinsic testicular activity and may require
7 s3 y4 Z" }* A% y  N' _prolonged administration for any response.% i5 c  k1 O( S
Alternately, topical testosterone does not depend upon tes-* }; ^( t% ^" K* i+ e% ~
ticular function and may provide a more constant level of
' U2 I- D+ C. B: \- _, w3 w' J# uREFERENCES
; B9 D8 ~5 S4 q1 o0 a1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, v5 ~. q+ P7 b
R.: The local application of testosterone cream to the prepub-" o2 R1 ?, t" |) q
ertal phallus. J. Urol., 105: 905, 1971.$ `6 i0 L) W3 o2 B4 {, M1 h
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone; b* e& Y; n' W- h
treatment for micropenis during early childhood. J. Pediat.,
' G6 L3 u, G& }* |" v3 F83: 247, 1973.
" D" _3 ^. x* O( d6 T1 e- g3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" M$ w  j: Q( o" a# c3 Wone therapy for penile growth. Urology, 6: 708, 1975.
! S# Y( l8 W% w$ Y! s4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 L7 g6 }/ e$ Lto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: O* f0 L2 }- b: F
skin slices of man. J. Clin. Invest., 48: 371, 1969.
1 F. X( N/ G( A: [( H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- p* k/ n9 V; [+ K! D  q3 J  z6 Zby topical application of androgens. J.A.M.A., 191: 521, 1965.
5 c' j# J) f; v, M6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 G4 v! C" [$ X" h( q
androgenic effect of interstitial cell tumor of the testis. J.5 g5 y% ^1 x/ \1 m) j% l" M
Urol., 104: 774, 1970.& i" @5 V& L/ N3 d$ p1 C4 H
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' }6 T1 \! \# i& @! e0 u* Gtion in the male genitalia from birth to maturity. J. Urol., 48:
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