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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 S# N1 \' Q% ^
GONADOTROPIN' ~5 P$ G, I" |, W
RICHARD C. KLUGO* AND JOSEPH C. CERNY' q8 b! x& X4 [+ i# D
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 `6 R& k6 R( J3 G0 s1 h# Q2 J
ABSTRACT
3 R1 H* K, w& w* d' Y9 O+ n9 zFive patients were treated with gonadotropin and topical testosterone for micropenis associated: d  D. Z2 _7 `( p* k, c8 H/ O# P. a
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# M& l7 G& g9 j4 B; G8 ?) btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 K; ~) l! y0 q6 ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( V, s6 x/ D" A
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ \3 Y% `+ f# H2 I1 tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ D( X+ G  N9 Q  C  n, {
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
6 |/ X0 ]4 u# Z3 B" boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- {  k0 B" A' e8 e2 `! }9 wstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# i9 `( D9 S" ~, M$ f+ Ogrowth. The response appears to be greater in younger children, which is consistent with previ-
8 `. V) B% ?' E4 W1 ]# rously published studies of age-related 5 reductase activity.
  u4 \) `. l3 C/ }5 GChildren with microphallus regardless of its etiology will5 t8 E- u/ P9 _
require augmentation or consideration for alteration of exter-
( J. m/ n' }+ l  j7 }' \6 Nnal genitalia. In many instances urethroplasty for hypo-
- [4 H7 b. L4 T4 R# Wspadias is easier with previous stimulation of phallic growth.  s  @9 h' [$ o- ?5 J
The use of testosterone administered parenterally or topically
: B+ M, t5 `1 h" _2 ]has produced effective phallic growth. 1- 3 The mechanism of
/ q% c$ _( P* h8 ]  mresponse has been considered as local or systemic. With this
) u/ I- `# c) I: F5 b, d5 `in mind we studied 5 children with microphallus for response
. X" y/ M: ]6 l( M" P( p3 ito gonadotropin and to topical testosterone independently.
0 c. Q2 \1 o+ Z5 v- u& LMATERIALS AND METHODS
! y( S  U2 A: A& x( D0 w- KFive 46 XY male subjects between 3 and 17 years old were
. E# u9 ^0 H. ]3 a" hevaluated for serum testosterone levels and hypothalamic8 i' D  ?1 y: {: y
function. Of these 5 boys 2 were considered to have Kallmann's' D( |! \: n- ~# q3 T$ m) Z
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& t8 s, s' h6 m) C8 C) P  w9 ?lamic deficiency. After evaluation of response to luteinizing
, E0 n+ X  \* P  N( F* xhormone-releasing hormone these patients were treated with
, n4 I4 l0 s1 a% V) f1,000 units of gonadotropin weekly for 3 weeks. Six weeks! c/ [- O! O( @( U( V
after completion of gonadotropin therapy 10 per cent topical7 ~3 O$ |) E! v" i8 b
testosterone was applied to the phallus twice daily for 3 weeks.. E8 f0 b  I" N+ V1 g/ _  O
Serum testosterone, luteinizing hormone and follicle-stimulat-
% ]7 `* I! |1 n" T0 h/ q& ~7 J3 q7 ving hormone were monitored before, during and after comple-
. t$ N" L3 `0 r: Z: xtion of each phase of therapy. Penile stretch length was- u( ~4 m, M' a/ r0 j
obtained by measuring from the symphysis pubis to the tip of. f: d$ l8 T4 p0 Z
the glans. Penile circumferential (girth) measurements were1 n: m( F/ \) _$ Z( c
obtained using an orthopedic digital measuring device (see
6 P& Z& ?# `* S: I5 c6 j$ qfigure).' x2 h# S- k; u4 o8 H: |( M
RESULTS
! {, ?" h$ r! oSerum testosterone increased moderately to levels between2 {. ~" @, V* ]
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) Y  q* h# g, S" r3 \6 L! R1 Iterone levels with topical testosterone remained near pre-
  `- I( `( P& o/ F/ D, Gtreatment levels (35 ng./dl.) or were elevated to similar levels
+ X8 t' Q% l9 q( D4 Mdeveloped after gonadotropin therapy (96 ng./dl.). Higher
' E2 H" Z. W7 H7 ^. s  ?4 eserum levels were noted in older patients (12 and 17 years old),
- V# |8 w5 `' d, t7 U) c, Z, Nwhile lower levels persisted in younger patients (4, 8, and 10! s$ |* e9 h- H) L
years old) (see table). Despite absence of profound alterations6 U, u0 N% {7 r$ `
of serum testosterone the topical therapy provided a greater
& ~9 f* T) [% x* J. e: NAccepted for publication July 1, 1977. ·1 U4 z$ [0 f: J6 g/ v! M6 H
Read at annual meeting of American Urological Association,. Y  e) Z$ N7 C; C) _5 ]
Chicago, Illinois, April 24-28, 1977.) @3 h( T! K* [8 i: E2 d
* Requests for reprints: Division of Urology, Henry Ford Hospital,
; h, z+ K: U2 T8 @% ~. J1 F2799 W. Grand Blvd., Detroit, Michigan 48202.' _0 ^3 I& Q& Q) Q. l
improvement in phallic growth compared to gonadotropin.% [; G+ I4 g! ?- z! n
Average phallic growth with gonadotropin was 14.3 per cent
+ L# {+ j; H. Z6 ^# ?/ R! lincrease in length and 5.0 per cent increase of girth. Topical, {3 Z! h5 V+ v# Z! M$ z
testosterone produced a 60.0 per cent increase of phallic length. n7 Q, X5 X. G
and 52.9 per cent increase of girth (circumference). The
3 l; e, Y3 ]. sresponse to topical testosterone was greatest in children be-' A9 Q, F+ `: `/ _- X! t7 E- F8 f
tween 4 and 8 years old, with a gradual decrease to age 176 V( L! N9 B) e
years (see table).6 {0 P* Q. b( [: K) J3 A- u  X
DISCUSSION% n& f5 g2 M. q6 z
Topical testosterone has been used effectively by other
& v+ P0 C6 W! n" [, X; O/ tclinicians but its mode of action remains controversial. Im-& o' ^# B; r! d) H1 d, ]
mergut and associates reported an excellent growth response. M" t3 g- F2 P/ o
to topical testosterone with low levels of serum testosterone,9 V8 {$ e/ i6 J
suggesting a local effect.1 Others have obtained growth re-
2 C) ]  |$ K0 E: {( Y) h! R. nsponse with high. levels of serum testosterone after topical- U: P4 y6 l! E/ H: A
administration, suggesting a systemic response. 3 The use of' `" s4 \' E# A. \2 B: A2 j0 I+ N/ T
gonadotropin to obtain levels of serum testosterone compara-
, [- V& Y7 e5 k# ^- T$ S1 Dble to levels obtained with topical testosterone would seem to( t! ^3 ^; Q: n
provide a means to compare the relative effectiveness of% F' L+ L% F# @
topical testosterone to systemic testosterone effect. It cer-6 k0 F, J' W+ \. d
tainly has been established that gonadotropin as well as par-
5 O5 s* _2 \  |/ Yenteral testosterone administration will produce genital
- y! k+ P& j- t) O3 I0 D0 E4 J& lgrowth. Our report shows that the growth of the phallus was) C! h5 f8 b2 C8 I/ U
significantly greater with topical applications than with go-1 F; K( ~$ v; r2 k3 K
nadotropin, particularly in children less than 10 years old.
% F2 k& D4 m! e/ G. c. M5 z! `The levels of serum testosterone remained similar or lower
' x/ ^7 S* t6 `3 o+ Cthan with gonadotropin during therapy, suggesting that topi-
# K  i. ]! [+ ]cal application produces genital growth by its local effect as0 c6 a9 x5 v+ C8 M: I. L9 y
well as its systemic effect.
9 I  V: ~: I1 V$ C* T0 ]4 T6 HReview of our patients and their growth response related to3 B2 R: V; w  @/ S
age shows a greater growth response at an earlier age. This is: L' @) J: I/ ~
consistent with the findings of Wilson and Walker, who
' B. E1 e9 E+ x- V( jreported an increased conversion of testosterone to dihydrotes-2 @! B" o- l/ V3 n
tosterone in the foreskin of neonates and infants.4 This activ-
/ v( G5 g0 K- k! Q' b* Mity gradually decreases with age until puberty when it ap-
2 s7 b( Y  p, Z1 [9 O) Oproaches the same level of activity as peripheral skin. It may; K+ @' \1 e% x8 Y) q! F
well be that absorption of testosterone is less when applied at; u1 ~" x- r8 g
an earlier age as suggested by lower serum levels in children
( \, ?: |* g9 P2 |7 j0 K$ y2 |less than 10 years old. This fact may be explained by the
  M- `4 A$ S1 ?' C9 K& Tgreater ability of phallic skin to convert testosterone to dihy-
1 _' M) J- }) ?$ p6 h9 ?7 Rdrotestosterone at this age. Conversely, serum levels in older% X# I  m# d. N. z
patients were higher, possibly because of decreased local
  c4 @4 n3 A& u  P9 h667+ g" m$ W* Y5 D: C: S/ K8 E
668 KLUGO AND CERNY: s( y5 ?$ p) e- Z
Pt. Age
5 B. Z% K4 P+ A  b4 F  u(yrs.): y3 g" w( q- s+ Z! E
Serum Testosterone Phallus (cm.) Change Length. M4 K0 A! P% Y3 A
(ng./dl.) Girth x Length (%)" S* T3 O7 a8 E3 y+ T* L
41 F3 r* W- ?( b, w3 X
8
) z4 E2 g; u  i- H3 H! K+ a10
7 V4 U) N, P( ~- c+ Q3 {12! R: ~/ O( E9 `: i$ Y% w
17" S5 {: d  y- }% l! @) X
Gonadotropin" q$ ?4 v- V- H" h7 D  o
71.6 2.0 X 3 16.6
& U3 K& h0 E& R- m1 A50.4 4.0 X 5.0 20.0  F, |3 L0 `7 ^  u' T
22.0 4.5 X 4.0 25.0) ^8 a% ^) z3 z. D- y1 t
84.6 4.0 X 4.5 11.1
+ Y4 _' r# [8 ^* A7 w% @$ O7 x& h: |85.9 4.5 X 5.5 9.0
' J0 T$ h1 G: B% u) o. Z1 @Av. 14.3
2 B( x# b0 U/ u) p4
: e. ]# A% b6 x' `! k; g8 J8- X/ p, s8 I, K$ g) w& b
10
8 N9 h$ b( T3 s. U" i* V5 }12. {1 c( X. \* I  D% [; l6 s/ a
172 ^: [9 p/ W6 Q6 H" P- S4 Y
Topical testosterone  v+ n) ~9 Z' l- W* O+ D
34.6 4.5 X 6.5 857 i: k7 N. \, U3 K+ Z  J" n' L% T
38.8 6.0 X 8.5 70
% S: ]/ n3 k: |, f) Y40.0 6.0 X 6.5 62.5: `! p8 |# \+ E- ~
93.6 6.0 X 7.0 55.5
4 Z, R, F  Q1 O/ I1 f/ b95.0 6.5 X 7.0 27.2# o, w( r# e8 Q) G
Av. 60.0
/ l3 H) h5 `8 s4 ^available testosterone. Again, emphasis should be placed on
  \+ g  z- e$ L1 }3 e9 a! @early therapy when lower levels of testosterone appear to3 p; A* Z  [8 j
provide the best responses. The earlier therapy is instituted
! f! R! L! A- g3 Xthe more likely there will be an excellent response with low
" b3 y  W5 l  r& g" Vserum levels. Response occurs throughout adolescence as
6 @$ O' ?& ^' O! B; V' u' g& Gnoted in nomograms of phallic growth. 7 The actual response
$ a; E" {/ n- {; L, {; m' Ito a given serum level of testosterone is much greater at birth
  a$ q; t9 ?& L% Q& ^and gradually decreases as boys reach puberty. This is most
0 j, C& [6 ^7 X; C# v* _likely related to the conversion of testosterone to dihydrotes-
4 g" X" b6 G+ ?: h6 J7 Btosterone and correlates well with the studies of testosterone  H( s' O  ^0 I4 ?/ }" c7 V+ _
conversion in foreskin at various ages.8 k) `4 e: @6 [' d$ `0 o7 I7 [
The question arises regarding early treatment as to whether
* U5 Y* T: m/ g3 @3 vone might sacrifice ultimate potential growth as with acceler-+ K6 N; s* V# h7 h1 H
ated bone growth. The situation appears quite the reverse
1 `) m: q% v, v3 C9 qwith phallic response. If the early growth period is not used& G. n8 j. b( E2 [* `
when 5a reductase activity is greatest then potential growth3 r( G6 H. {6 T# O+ U- w0 ?. X! \( {
may be lost. We have not observed any regression of growth
7 s0 N0 v1 w4 f" v8 \* S! y8 battained with topical or gonadotropin therapy. It may well, r5 u. h. j; c
be that some patients will show little or no response to any5 K2 _/ f3 S3 o2 \% r4 O
form of therapy. This would suggest a defect in the ability to  {# D' ]" L" x' u+ o) m, J
convert testosterone to dihydrotestosterone and indicate that1 R2 \) `3 ~, O) }' Y  ]0 d  m! H( y& p1 D
phallic and peripheral skin, and subcutaneous tissue should6 F% A* Z0 J9 [! B& _/ }
be compared for 5a reductase activity.
5 t7 R) f2 _; Q% K# c' ]A, loop enlarges to measure penile girth in millimeters. B,: V6 M( {% h# K- y" N8 Z
example of penile girth computed easily and accurately.. p  D1 R0 N+ j% f! x
conversion of testosterone to dihydrotestosterone. It is in this
1 e/ e( j# ~; Y3 x, q# f- rolder group that others have noted high levels of serum
( ?; T3 @4 `+ z4 Ttestosterone with topical application. It would also appear
8 W! i& [% ^  R) Vthat phallic response during puberty is related directly to the/ s. e  ]% j$ C  r; y* C" n- c0 K
serum testosterone level. There also is other evidence of local' x  M( k8 p& c5 Q
response to testosterone with hair growth and with spermato-
( \# R7 p# w7 pgenesis. 5• 6" m4 _  z* e; H; \. B2 N+ N
Administration of larger doses of gonadotropin or systemic) u/ k/ O- C! ]. F! h  W7 h
testosterone, as well as topical applications that produce
: l1 k, y3 w- X& h$ T" P: ?! n3 mhigher levels of serum testosterone (150 to 900 ng./dl.), will
2 m) ~# j" q- y  Y4 u: Aalso produce phallic growth but risks accelerated skeletal
0 E9 x% |$ o2 p+ L% S& {9 Amaturation even after stopping treatment. It would appear
. T5 I- ?0 ]. Lthat this may be avoided by topical applications of testosterone
7 S. _1 T: Z  p: l( ~and monitoring of serum testosterone. Even with this control* v$ A# E. c$ m- ?: Y$ q1 E
the duration of our therapy did not exceed 3 weeks at any
% ~4 A, t% Z4 p! W! Ltime. It is apparent that the prepuberal male subject may/ f5 F& V2 j) S( L" I2 ?+ A
suffer accelerated bone growth with testosterone levels near4 n* H$ n# I8 s! d" e
200 ng./dl. When skeletal maturation is complete the level of
2 \) H# g$ O& k9 @serum testosterone can be maintained in the 700 to 1,300 ng./4 S4 s- P6 [: u$ s6 K) E& z
dl. range to stimulate phallic growth and secondary sexual: i  H, s  C# q. l6 |* L! V: ~
changes. Therefore, after skeletal maturation parenteral tes-6 j( D* w. |& h
tosterone may be used to advantage. Before skeletal matura-3 ~5 U+ m- \2 u9 P3 N1 R, V9 E
tion care must be taken to avoid maintaining levels of serum
- d. }! n8 a2 J8 S, atestosterone more than 100 ng./dl. Low-dose gonadotropin: Y1 p: E0 t& k& Y+ E1 X
depends upon intrinsic testicular activity and may require" R6 w  c' M  V5 f- Y- s
prolonged administration for any response.
8 Y1 @8 x+ F- u- }6 Y# k! [' wAlternately, topical testosterone does not depend upon tes-, a9 ~9 C( `# }& y" e* j6 k6 I
ticular function and may provide a more constant level of
2 W' N5 X, [" g& z, W/ oREFERENCES
3 a: }& R/ ]3 z2 Q1 E* @3 t1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
* U; A/ S+ b; {$ v) uR.: The local application of testosterone cream to the prepub-  e: _$ ?+ I7 F5 H, y" k$ c8 u
ertal phallus. J. Urol., 105: 905, 1971.
) O( @5 w) D* }) q: L2 D: u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
4 }/ a2 w6 D  G2 U) }" E: W# B" qtreatment for micropenis during early childhood. J. Pediat.,) y$ r! t* W' [  Y" i1 X% ?/ i
83: 247, 1973.
# a. W) s# |/ _2 I# r3 i' ~7 K3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
$ d$ j! n$ h9 ]2 f5 d3 r% done therapy for penile growth. Urology, 6: 708, 1975.# y  y& ~/ t: z6 _. Y0 a
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* _' H9 t+ u; L1 i% {% M( l
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" y- t$ p3 s1 C/ @. O' w8 J
skin slices of man. J. Clin. Invest., 48: 371, 1969.# F2 d8 ^; H6 p' _
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) T5 o! S  g) {) }by topical application of androgens. J.A.M.A., 191: 521, 1965.
3 Y: y! q; ?, k6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local" u  a! s9 ^' g% s1 K1 [
androgenic effect of interstitial cell tumor of the testis. J.
2 [! O: N! n! d7 g! c# t/ RUrol., 104: 774, 1970.
3 f4 K" r8 M! q4 F$ }7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 Y9 g) s- _: m; j0 _tion in the male genitalia from birth to maturity. J. Urol., 48:
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