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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* w# O0 g- _$ @% ^' r4 Y8 l9 A* ^GONADOTROPIN4 C7 M; }+ X- c! C, b
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 v! [8 k! Y7 D. _- ]' W5 \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, @- {, U9 S  x% G  [# A8 nABSTRACT
3 _0 B. j5 I( kFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 G8 ]: N3 Q1 Y& Y- m) p7 p9 O# b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
$ {( g4 }1 G' I4 G2 A' D" w( ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 p$ O7 B' g3 p' U5 g: h# |$ s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent% F- u8 i: M6 p& i' v/ _- V& ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 ^3 C  c  S* @7 ]9 E- r
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average( a- V2 C. J+ t" `- t
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 _6 W6 u" l# a% _9 U3 poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" v, ]/ b' a3 p8 }% H3 y; I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( ?! P' L. B. d- |4 W: {growth. The response appears to be greater in younger children, which is consistent with previ-* c, Q( R  a( ?" ?$ p3 Y: U
ously published studies of age-related 5 reductase activity.
! T8 C8 d5 d9 y" m1 cChildren with microphallus regardless of its etiology will
. o  z5 K2 d2 u* p2 z$ A! B: [require augmentation or consideration for alteration of exter-* o/ E1 ]2 D: @8 p
nal genitalia. In many instances urethroplasty for hypo-: i: q7 Y2 K+ l
spadias is easier with previous stimulation of phallic growth.
1 H# j7 B% r1 P4 G' z) M; kThe use of testosterone administered parenterally or topically
8 F' A' w$ o% v: a7 fhas produced effective phallic growth. 1- 3 The mechanism of
! {! j  O8 J2 m5 P3 lresponse has been considered as local or systemic. With this
  q9 C* w( ~5 ]* H0 Z; jin mind we studied 5 children with microphallus for response& z5 ^4 p+ e0 }7 w  y
to gonadotropin and to topical testosterone independently.
8 w1 f/ Q! N+ Y" RMATERIALS AND METHODS: V$ @8 I9 d" o0 {' r5 }. a+ ^
Five 46 XY male subjects between 3 and 17 years old were. R3 [% X  o# y/ L, |: |
evaluated for serum testosterone levels and hypothalamic
" b6 y% C: n. H# p. G5 F/ C3 Ofunction. Of these 5 boys 2 were considered to have Kallmann's
/ j3 P0 V1 D9 g( Csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-$ [: D. _3 A5 y5 D; _% E3 |
lamic deficiency. After evaluation of response to luteinizing
% n$ l+ N, p# Y; W+ hhormone-releasing hormone these patients were treated with
0 g6 Q! T7 F2 [' C: `* M+ e6 U1,000 units of gonadotropin weekly for 3 weeks. Six weeks) C# {6 G& H* w3 P2 q! F$ N
after completion of gonadotropin therapy 10 per cent topical( z8 {! R. S* H6 H2 j) |
testosterone was applied to the phallus twice daily for 3 weeks.
( F" q; q* S+ F$ YSerum testosterone, luteinizing hormone and follicle-stimulat-
, K7 N% r' Z  j7 g- Ving hormone were monitored before, during and after comple-
. g$ K7 @9 q4 o; U: b9 Ction of each phase of therapy. Penile stretch length was/ v4 I& D1 y! G. Z* M! ?) ?
obtained by measuring from the symphysis pubis to the tip of
) S7 d3 Q& ^; K/ x- V' q+ bthe glans. Penile circumferential (girth) measurements were
% \# X  m7 q+ e/ @obtained using an orthopedic digital measuring device (see
9 v0 |1 ]+ K3 Z9 W7 pfigure).
' O# {6 v- ^4 \2 ARESULTS
$ {, G: a# x( e3 ySerum testosterone increased moderately to levels between% Q) j+ [* a4 n* V+ W8 ]6 d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* z4 j2 ~& z. j3 b
terone levels with topical testosterone remained near pre-
! b/ T$ |# s' K. Ptreatment levels (35 ng./dl.) or were elevated to similar levels
  l- {# y  B. R/ ~0 A! xdeveloped after gonadotropin therapy (96 ng./dl.). Higher
( r+ g- R. e" B& zserum levels were noted in older patients (12 and 17 years old),* H& N, c" g) }; o7 L) K- ?
while lower levels persisted in younger patients (4, 8, and 101 B1 G4 Y0 |- M; X  Y+ J& P
years old) (see table). Despite absence of profound alterations( G$ `! O# U: O4 E5 J  |) c
of serum testosterone the topical therapy provided a greater
0 u5 J! q" [% F4 N8 [5 ^2 }7 y5 `Accepted for publication July 1, 1977. ·# D, S% \$ l3 S: \- i
Read at annual meeting of American Urological Association,2 R; a' Y; Z: c* P; C
Chicago, Illinois, April 24-28, 1977.
6 y2 H+ g5 l) c9 ]) [* Requests for reprints: Division of Urology, Henry Ford Hospital,
% B0 e& t* ]7 B( k2799 W. Grand Blvd., Detroit, Michigan 48202.
' R0 X# _% U3 c  u# M1 i. ?improvement in phallic growth compared to gonadotropin.+ `2 x9 n% I2 p/ k/ q, y
Average phallic growth with gonadotropin was 14.3 per cent2 E8 ~" W- i: Y
increase in length and 5.0 per cent increase of girth. Topical
' D0 ]' d) b  x; [testosterone produced a 60.0 per cent increase of phallic length
! o2 m0 c0 n. @# h3 X+ o+ cand 52.9 per cent increase of girth (circumference). The  f. z, c: U8 u- X! U$ u
response to topical testosterone was greatest in children be-
' t( ~  Z1 B, f1 ?/ M+ o1 ]: itween 4 and 8 years old, with a gradual decrease to age 17
. ~; P# j0 t2 ]" I" ?years (see table).
, ?8 g% x6 U- B; ZDISCUSSION1 `( b2 T9 {- t: M9 Q
Topical testosterone has been used effectively by other
* B9 P: x+ ~8 n+ I' C# Tclinicians but its mode of action remains controversial. Im-
. N7 B) q9 F5 r* F1 Jmergut and associates reported an excellent growth response* i  }2 m9 h3 f8 x2 ?- N
to topical testosterone with low levels of serum testosterone,# p( a, O" `1 \! A- {
suggesting a local effect.1 Others have obtained growth re-
( ~6 Y1 v" I. {sponse with high. levels of serum testosterone after topical9 V6 O' M, P; v- }" M- Y' h
administration, suggesting a systemic response. 3 The use of" @- o8 v6 l7 r
gonadotropin to obtain levels of serum testosterone compara-
& i, ~/ ~3 Y2 E+ @; P1 Qble to levels obtained with topical testosterone would seem to: j2 j/ M7 O5 P) j* H
provide a means to compare the relative effectiveness of2 J; z- |1 H9 g0 \) l2 t
topical testosterone to systemic testosterone effect. It cer-
9 z- N$ [) l% s+ k0 etainly has been established that gonadotropin as well as par-
2 ~& K  b. a& X8 Aenteral testosterone administration will produce genital
$ P* @1 D# s. Z+ sgrowth. Our report shows that the growth of the phallus was
- C- k" C1 F4 ?) a0 _7 fsignificantly greater with topical applications than with go-6 N6 `- `! v6 R1 ~, I% ^
nadotropin, particularly in children less than 10 years old.2 g4 a! S8 B7 v6 ~
The levels of serum testosterone remained similar or lower
' `1 w" c/ w# s& a# w* I6 |than with gonadotropin during therapy, suggesting that topi-; q4 L1 n: a) c4 [! d
cal application produces genital growth by its local effect as' @/ e( A2 I( B9 j5 t9 L7 n0 y9 b
well as its systemic effect.$ S# Y: p6 \9 t& S
Review of our patients and their growth response related to" x6 H& k- q. \7 Y2 o2 @. [  K# f
age shows a greater growth response at an earlier age. This is! [  Y4 l! q1 E, N/ ?. H7 `* W" j4 d
consistent with the findings of Wilson and Walker, who
% I) e& _  i) _5 E$ Dreported an increased conversion of testosterone to dihydrotes-3 d0 }/ j" k1 k3 [9 _2 Z
tosterone in the foreskin of neonates and infants.4 This activ-- t$ X- `+ L% l5 I! t, a+ K) |; X, d
ity gradually decreases with age until puberty when it ap-0 L$ s  m* J# [. W' Q
proaches the same level of activity as peripheral skin. It may, q/ X4 V- R0 E+ m$ T& n
well be that absorption of testosterone is less when applied at" g# h/ r0 T4 ^
an earlier age as suggested by lower serum levels in children
/ ~1 k3 }$ A1 ]2 l6 \less than 10 years old. This fact may be explained by the& L1 C: s- {; z& ~
greater ability of phallic skin to convert testosterone to dihy-, k) B6 r, \: i1 F0 ~
drotestosterone at this age. Conversely, serum levels in older
8 Y% S, u& `4 [: S  [, t! lpatients were higher, possibly because of decreased local
8 ^* p. B5 B  m* B4 ]667
6 o8 y( v$ H# a+ ~. G' A1 F2 H668 KLUGO AND CERNY3 Z; f0 P- F, E
Pt. Age5 e; a: }8 r+ D  }8 ^5 C  N7 I
(yrs.)
2 z$ _7 i' S" O: u, P% M3 ~' fSerum Testosterone Phallus (cm.) Change Length
. }% ?$ ?( N2 A9 W- @: C(ng./dl.) Girth x Length (%)
& N) I9 l& x, h% j: s% H' n43 I: `5 l, X1 R/ H
8- X- w' B0 Q# h1 B
108 _+ E( M/ k/ U  v/ o4 L3 X" G
128 _5 e) J; W1 m; N
17/ M' l1 K" t9 ]; E9 G, o
Gonadotropin8 f$ J4 X0 e7 k+ n3 D
71.6 2.0 X 3 16.6
5 E0 ]& M; C! ?7 F: d6 {* h! b50.4 4.0 X 5.0 20.06 Z. q- j& b; k/ B( Y
22.0 4.5 X 4.0 25.0
8 J% |5 c6 V: J9 o& f$ [84.6 4.0 X 4.5 11.1
( [- r, U/ I1 P; p# ^1 C8 b$ y85.9 4.5 X 5.5 9.0
0 f# R! g6 y+ VAv. 14.39 J! t6 F& v" u" U
48 ^1 D% I# f7 S/ R# C
8
/ ^' M+ l& u5 M8 \" X* M- |. n101 h# ~1 X0 z# W% p
128 s' i' t& N$ t  I9 z
17
8 N7 s7 s) S5 B# }7 L$ x5 nTopical testosterone4 F9 X6 B; o% ?2 X- M
34.6 4.5 X 6.5 856 D3 Q( {1 Z, I+ x" V: ?# b
38.8 6.0 X 8.5 70$ B% y% v6 F7 j! ]) \
40.0 6.0 X 6.5 62.5
  s" `8 l0 l$ u93.6 6.0 X 7.0 55.5
! |8 m& j" a% ~4 ~9 U9 ]# V  i95.0 6.5 X 7.0 27.2
$ q0 ~) W  [# l! O: B2 QAv. 60.03 z2 \8 `$ P1 D/ \# m
available testosterone. Again, emphasis should be placed on$ E/ ~, X/ K( N9 l6 R% e3 U
early therapy when lower levels of testosterone appear to
. D9 X# t) j2 w4 P/ q" ~8 p0 k- b  Mprovide the best responses. The earlier therapy is instituted
' z4 H9 z% o$ Z0 xthe more likely there will be an excellent response with low
$ i( _- D6 m& j7 ]+ X- |! pserum levels. Response occurs throughout adolescence as
* v( B7 v$ Y6 {- [* d+ T8 _4 g$ d8 gnoted in nomograms of phallic growth. 7 The actual response8 u  m! h- P; D# I9 G6 J* {
to a given serum level of testosterone is much greater at birth" W; ]& k& J2 p8 H, U- i; @4 ~
and gradually decreases as boys reach puberty. This is most( A, m# `$ S- Q" H
likely related to the conversion of testosterone to dihydrotes-+ ]6 Z1 z$ q3 K+ ~) C: Q
tosterone and correlates well with the studies of testosterone' W; f& L* z, n1 D
conversion in foreskin at various ages.
0 x1 f& C' s  \5 u, x0 g9 y4 z5 cThe question arises regarding early treatment as to whether
  ^! U7 s( k8 [5 |one might sacrifice ultimate potential growth as with acceler-
6 x3 K7 x" \2 W; Yated bone growth. The situation appears quite the reverse
0 Z9 p; Y- H6 Lwith phallic response. If the early growth period is not used; d: c! l% M0 z2 L" N% D
when 5a reductase activity is greatest then potential growth2 G1 ]! N. Y) B, F8 K8 m  d
may be lost. We have not observed any regression of growth
1 c/ Q( k' O, R: N4 _attained with topical or gonadotropin therapy. It may well/ c, A; ]% C$ M6 o
be that some patients will show little or no response to any
( ]& f2 D/ F7 ?  f' b; C! |form of therapy. This would suggest a defect in the ability to
; d6 ~+ D- `6 u- kconvert testosterone to dihydrotestosterone and indicate that
) ^9 U$ F0 b' J$ rphallic and peripheral skin, and subcutaneous tissue should
+ c' S0 d9 s8 w$ V* j$ e8 cbe compared for 5a reductase activity.
0 ]8 h: y7 Z' r* I7 a2 g1 GA, loop enlarges to measure penile girth in millimeters. B,
$ [1 N4 L. u3 Rexample of penile girth computed easily and accurately./ R7 g9 T4 o; n7 T" A: z% n
conversion of testosterone to dihydrotestosterone. It is in this4 k& x; [; h8 O9 H/ b$ B
older group that others have noted high levels of serum
1 p6 k! @8 ]% n% Y% v) K" o, atestosterone with topical application. It would also appear  \  `& i( t. {6 {
that phallic response during puberty is related directly to the
0 r" r" x8 H& s% F+ I$ _serum testosterone level. There also is other evidence of local
1 f) F0 J6 o; n9 P* `5 Oresponse to testosterone with hair growth and with spermato-
! U( u  U/ [, M, W7 T6 J$ y- Pgenesis. 5• 68 Q* I" d5 M( p
Administration of larger doses of gonadotropin or systemic
4 c" q3 W1 w* i- ~testosterone, as well as topical applications that produce
- f9 h/ @2 w  n' Z1 khigher levels of serum testosterone (150 to 900 ng./dl.), will
+ O9 F) ?6 l7 Q/ Ualso produce phallic growth but risks accelerated skeletal
. E& A& M. Z) ?9 a# T% u8 Fmaturation even after stopping treatment. It would appear
$ Z% `9 `/ Q3 pthat this may be avoided by topical applications of testosterone
3 O# {6 b# Q' {. G$ y& wand monitoring of serum testosterone. Even with this control
) [4 r  i# ^. p  @3 q' Zthe duration of our therapy did not exceed 3 weeks at any
, G! T, f# k; r* ?3 otime. It is apparent that the prepuberal male subject may
( o! F, w2 x$ m) [" q6 G8 A1 Hsuffer accelerated bone growth with testosterone levels near
; R: L, {- U9 g" j. f4 {# b200 ng./dl. When skeletal maturation is complete the level of. G# x6 t% s% Y! p) d7 e9 @2 S
serum testosterone can be maintained in the 700 to 1,300 ng./) `' {) }3 k+ L6 P. m3 C0 k
dl. range to stimulate phallic growth and secondary sexual
9 e5 L3 L5 G! k' `  |changes. Therefore, after skeletal maturation parenteral tes-
& w; ~$ C9 B; P- s! U. K# htosterone may be used to advantage. Before skeletal matura-: I& \# P# ^/ _4 Z1 l* |& b
tion care must be taken to avoid maintaining levels of serum5 O( l+ N; o% {! I8 M$ p9 q4 H
testosterone more than 100 ng./dl. Low-dose gonadotropin
! ~7 P3 T) P8 C; q2 c8 T3 {8 ydepends upon intrinsic testicular activity and may require
, Q( ^" a# Z' O5 A4 }prolonged administration for any response.) E" N  W4 C3 E1 n" Z
Alternately, topical testosterone does not depend upon tes-8 b4 D9 J: w" b5 z
ticular function and may provide a more constant level of
5 R, K0 \4 q# Y& L6 k. X5 NREFERENCES
9 w" m% d: {$ b4 k5 f1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,2 ]6 {8 ~3 ^3 n& w6 {
R.: The local application of testosterone cream to the prepub-
& `" P9 I7 e9 Qertal phallus. J. Urol., 105: 905, 1971.
6 C- s) {6 i9 y, X) v2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) P) ^; _$ l# C5 k. y' l; P! L9 n$ Utreatment for micropenis during early childhood. J. Pediat.,, |. R# m4 \" Q# Y' P+ X- d0 I
83: 247, 1973.
. [) @$ R* {+ \0 t  b3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' L% J2 ]. T8 `one therapy for penile growth. Urology, 6: 708, 1975." p0 k  M, f& F: I
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 `5 L8 Y2 B# F9 e# F) Ito 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by  f" _7 `2 @) q/ g! g, @8 \- V
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' W8 B+ N% S+ N" }5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
1 j" W' ]. I' z# ~8 ?; y6 Sby topical application of androgens. J.A.M.A., 191: 521, 1965.
( r4 U1 e( C, }( q  A4 K! h6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. w( \7 E7 o( e* |
androgenic effect of interstitial cell tumor of the testis. J.. r/ U2 ]) z3 D" q: z( x/ {) D% E
Urol., 104: 774, 1970.
; F4 R% i# X! L! o/ S4 y& w7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 }( R# B! m8 m& Vtion in the male genitalia from birth to maturity. J. Urol., 48:
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