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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 J  T% X6 e+ x0 t8 e5 ^# F1 |GONADOTROPIN, x: D4 O: c' ~3 s. g
RICHARD C. KLUGO* AND JOSEPH C. CERNY
% S1 e! X, f. N8 T! SFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* q# p" A$ @0 ^ABSTRACT
! O5 C. K) U$ a% E2 @1 p; ?Five patients were treated with gonadotropin and topical testosterone for micropenis associated
  I* i& G6 O. k4 g  A! V5 y) u0 Bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
: f4 _5 z) P: ~$ g& xtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" s7 f! }9 e( E% Fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 P2 @" K  X$ q8 r" h) I" e4 Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 |* L* w9 Y  o2 }- h- Nincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average9 j$ ?( n5 @6 j- |: q8 C& V
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response" X. |5 C( q( c/ y5 W! I
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 m3 N' i. O( f$ L1 e
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, y% m+ J6 P# }; ]; C
growth. The response appears to be greater in younger children, which is consistent with previ-
& [8 I0 O8 y" r( @6 J% Eously published studies of age-related 5 reductase activity.
% @5 q8 [1 k1 ^+ J( pChildren with microphallus regardless of its etiology will. @* {) m' o* ~$ z; D8 ], P
require augmentation or consideration for alteration of exter-
6 ^+ w" J$ j) m6 R3 d9 ~nal genitalia. In many instances urethroplasty for hypo-' u' M6 U2 _  ^
spadias is easier with previous stimulation of phallic growth.
' r0 S+ U  ^6 l2 q5 H; P5 _' kThe use of testosterone administered parenterally or topically
+ \% N! f7 @- C6 {4 Fhas produced effective phallic growth. 1- 3 The mechanism of  O7 g: B7 V" g* K2 }2 r
response has been considered as local or systemic. With this
, V  _: i; c/ i' c: r4 Q6 [/ Vin mind we studied 5 children with microphallus for response
1 G; e' Z" h0 q  w( U" O- @0 E$ @to gonadotropin and to topical testosterone independently.9 ^' h+ t" D% T  H( c6 d
MATERIALS AND METHODS% X" P0 ]& d1 b1 A# g4 ]6 p  E
Five 46 XY male subjects between 3 and 17 years old were
6 W7 u& ~7 t0 I9 e' Hevaluated for serum testosterone levels and hypothalamic2 j2 r) q* J2 T/ @" [
function. Of these 5 boys 2 were considered to have Kallmann's
' v! l  k; t2 b0 asyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-4 e; `3 C" n0 {: @) I+ o
lamic deficiency. After evaluation of response to luteinizing
4 A5 V+ S' h5 O# P! e  Q, ehormone-releasing hormone these patients were treated with
. ^, ^" r  z3 Y7 V. ~  q' g1,000 units of gonadotropin weekly for 3 weeks. Six weeks
5 Y! ]9 k1 }9 p* @& Bafter completion of gonadotropin therapy 10 per cent topical
* M7 t7 e/ L( |: u" h, Mtestosterone was applied to the phallus twice daily for 3 weeks.
# j" Q5 C( b( W* O5 y  ^5 C% LSerum testosterone, luteinizing hormone and follicle-stimulat-1 y. Z& q5 `4 k9 [, Z" x
ing hormone were monitored before, during and after comple-
4 R8 J/ n6 F7 D" c+ ]& Ltion of each phase of therapy. Penile stretch length was7 L  H9 o# ~  F+ b/ V
obtained by measuring from the symphysis pubis to the tip of! @6 c3 p/ m" K) P. r: _
the glans. Penile circumferential (girth) measurements were; Y# p4 h* a9 j0 t
obtained using an orthopedic digital measuring device (see6 C% b4 {) O8 _: Q4 s5 |4 `
figure).; G. @. k5 I9 f; E! h2 i
RESULTS
# [, [3 l2 C$ ]8 GSerum testosterone increased moderately to levels between( I0 D) h5 d: J, c: Q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ i  [4 m( m: e; Jterone levels with topical testosterone remained near pre-  `: H% s* m7 j: ^8 [
treatment levels (35 ng./dl.) or were elevated to similar levels1 s: R- M+ t+ r4 e" c
developed after gonadotropin therapy (96 ng./dl.). Higher4 C' w9 X) k5 M) ~
serum levels were noted in older patients (12 and 17 years old),2 Z3 ?( L2 Y1 M6 K# }9 n! u
while lower levels persisted in younger patients (4, 8, and 10
. t( L, h# p+ o! `) ~years old) (see table). Despite absence of profound alterations$ K6 ~; b6 c) x: L: {7 F) y2 {7 P
of serum testosterone the topical therapy provided a greater5 H, h9 l* i8 ]! f4 {( I
Accepted for publication July 1, 1977. ·8 D+ Y3 m4 [" x, H" G$ v9 e
Read at annual meeting of American Urological Association,
; j# ]8 d6 x& w& f, gChicago, Illinois, April 24-28, 1977.
% q/ s: k* V! q+ d& e/ V( g* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 G0 h6 V/ T# |0 @- K2 `2799 W. Grand Blvd., Detroit, Michigan 48202.# R, v* N* I$ `: J% z4 H( M
improvement in phallic growth compared to gonadotropin.
! O- v' @  |" c, M5 S* bAverage phallic growth with gonadotropin was 14.3 per cent( {: G* Q+ E' k& q; t& u, ?
increase in length and 5.0 per cent increase of girth. Topical5 o; g2 f) S( h+ Z
testosterone produced a 60.0 per cent increase of phallic length9 k" G. r+ Y" ^8 L# ^0 M
and 52.9 per cent increase of girth (circumference). The
( x9 W" V7 y7 |' U" mresponse to topical testosterone was greatest in children be-" Y1 u9 C2 e3 M* }5 |
tween 4 and 8 years old, with a gradual decrease to age 17/ E, Z+ ]- A' j' t2 @  e
years (see table)., u) l1 b! P5 p' T4 _* n
DISCUSSION& G  Q& D0 p7 I" O; y* \
Topical testosterone has been used effectively by other
+ s4 k) b6 l5 i. Jclinicians but its mode of action remains controversial. Im-7 y# d6 G, W  Z6 x
mergut and associates reported an excellent growth response& b6 H6 f/ J1 N) K
to topical testosterone with low levels of serum testosterone,; g- ~6 |* L5 S8 {
suggesting a local effect.1 Others have obtained growth re-' i% }4 A+ R; a$ ~- m9 t7 p
sponse with high. levels of serum testosterone after topical8 J) z& s+ \  ^" Y% X$ m; _, C/ k
administration, suggesting a systemic response. 3 The use of
9 O8 U% }  ]- v6 `! g  M( B& Rgonadotropin to obtain levels of serum testosterone compara-
! L& w, o( k: X, ^0 P) pble to levels obtained with topical testosterone would seem to+ N# u+ I) Q% I
provide a means to compare the relative effectiveness of9 B- k4 |8 @0 s! R9 g
topical testosterone to systemic testosterone effect. It cer-1 w/ X# o* W' p" O5 p6 d
tainly has been established that gonadotropin as well as par-) L3 n' N: X; d- r- W( z% Q" S# i4 \
enteral testosterone administration will produce genital
* t8 k. @: J" sgrowth. Our report shows that the growth of the phallus was! a& \! G4 p0 Q' A; w' `4 A+ U3 k
significantly greater with topical applications than with go-
! c, S* Q0 t) z/ {4 d0 Nnadotropin, particularly in children less than 10 years old.
. z4 v( ?1 b0 e( F, e+ F+ IThe levels of serum testosterone remained similar or lower& t5 V' ^' l3 J# G: g& N0 i
than with gonadotropin during therapy, suggesting that topi-' z4 J" b+ x9 I# |
cal application produces genital growth by its local effect as  O( K$ ^/ G4 X8 E2 G6 {- W
well as its systemic effect.( d6 z& F* M8 p6 A- T
Review of our patients and their growth response related to; f0 O: H* P) K) M; d9 ?" H. R
age shows a greater growth response at an earlier age. This is0 w+ L3 [! \5 T/ N  Q
consistent with the findings of Wilson and Walker, who* }# [9 i5 _( W) S: Y7 M  F
reported an increased conversion of testosterone to dihydrotes-3 u. e1 y* U1 f; b0 G+ j
tosterone in the foreskin of neonates and infants.4 This activ-, b# U- ~6 d3 c3 M& H
ity gradually decreases with age until puberty when it ap-
. M6 o; w4 l; W3 S; wproaches the same level of activity as peripheral skin. It may/ t, @- P$ V0 X  s0 j  I
well be that absorption of testosterone is less when applied at
) @; J8 C- m; \! V6 Qan earlier age as suggested by lower serum levels in children: k0 {$ D/ W" i$ x
less than 10 years old. This fact may be explained by the8 T2 |* u& U4 s$ N7 D& u
greater ability of phallic skin to convert testosterone to dihy-) h7 [- w/ Q3 |% x$ h, H, u
drotestosterone at this age. Conversely, serum levels in older2 Z# h& {3 c; P4 {
patients were higher, possibly because of decreased local
6 ?4 I/ q' P1 z8 l" ?667
2 \- ]* H& f6 _668 KLUGO AND CERNY! H7 X5 j7 R2 S5 d
Pt. Age
! K* Y& s3 |/ i; O, A7 `+ A& b(yrs.)" W1 ~4 W+ }: e3 h% w3 s/ P
Serum Testosterone Phallus (cm.) Change Length/ ~* R8 x# c, z3 X6 ]: g" f
(ng./dl.) Girth x Length (%)- t; c! y1 L8 n
4. O' ~# P6 I( ^' o% L& z# B
8* Q9 S5 u, |9 ~7 D( B8 c
10  r: z( h+ S  S% ]( F& h  {& B% L4 k
127 u2 e9 _/ Z2 b. z$ U$ R1 f
17: T0 w" t: o$ k% X
Gonadotropin
6 B3 s& x8 d  x( f71.6 2.0 X 3 16.6& a# v  t1 N; A: Q' m$ g6 {
50.4 4.0 X 5.0 20.0
5 U0 d  P' A' v% ^! g" h22.0 4.5 X 4.0 25.09 J  J3 K3 H1 Q$ A( T  h
84.6 4.0 X 4.5 11.1
$ c% \. W/ E3 `( X85.9 4.5 X 5.5 9.0' F% n, a. w( n# h% {
Av. 14.3; E+ I. I6 X' x
4
  K; w' w6 h' d0 h8 k85 u, V0 h  K4 c1 p1 t
103 |; K, G  e6 _2 t% G( S1 @0 t
123 h# N1 z6 M" v5 L5 I
17
/ j0 Y5 b7 j6 wTopical testosterone( J9 d, A1 Y" v! h2 @2 v
34.6 4.5 X 6.5 85  }0 {' H, z8 G4 x4 _, d
38.8 6.0 X 8.5 70
& d: @+ V  w9 j! p0 N/ n40.0 6.0 X 6.5 62.5
' b+ G: h* n- U+ U: b* r, i  e93.6 6.0 X 7.0 55.5
( v5 W2 b1 J" q2 @  t. |. T95.0 6.5 X 7.0 27.2. ], @" {6 R- e. [! v- Y
Av. 60.0
9 b& W) R# N& q3 f: C5 qavailable testosterone. Again, emphasis should be placed on
0 Y( Y, [/ J* D9 x; m; ^early therapy when lower levels of testosterone appear to# s# [7 ^4 u) @+ K8 O
provide the best responses. The earlier therapy is instituted
% m3 h; a0 z0 B9 j9 `the more likely there will be an excellent response with low2 q7 f/ }) z) r- V4 @% I/ d; s  j
serum levels. Response occurs throughout adolescence as
: j" S' g/ y; I' V2 R6 O( W/ bnoted in nomograms of phallic growth. 7 The actual response+ ^  Y! m9 d6 N  z0 j
to a given serum level of testosterone is much greater at birth  s4 ^# Z9 V( O' D% p4 I
and gradually decreases as boys reach puberty. This is most# b+ ~  }! b8 V
likely related to the conversion of testosterone to dihydrotes-, t3 ^( O! G0 {! T, G5 v
tosterone and correlates well with the studies of testosterone
6 j) h4 R" W+ D$ m: [conversion in foreskin at various ages.  W1 k+ ?8 M: z7 o* C
The question arises regarding early treatment as to whether0 d5 ]" C, B6 w# o- E
one might sacrifice ultimate potential growth as with acceler-
2 q5 l6 v1 Z/ U) Eated bone growth. The situation appears quite the reverse
8 Y  w9 R; @# N' R( s) ]( l# Ewith phallic response. If the early growth period is not used
8 @4 k' q' ]4 H" E- q) L8 u- u% Bwhen 5a reductase activity is greatest then potential growth
. }' N* P& ~7 x. |0 pmay be lost. We have not observed any regression of growth0 _8 o, t2 M  b+ q
attained with topical or gonadotropin therapy. It may well
5 U% {$ h! |3 ~. b1 E$ Zbe that some patients will show little or no response to any7 ^8 |7 }; w1 @* K* ^0 @" ^
form of therapy. This would suggest a defect in the ability to6 w$ y  N/ _. D7 U0 J$ w9 D1 R: I
convert testosterone to dihydrotestosterone and indicate that
; l% L: ^; L$ p. ~/ e3 aphallic and peripheral skin, and subcutaneous tissue should
! Y5 a* D8 }% O; Bbe compared for 5a reductase activity.- P0 g3 u% ^  f9 W5 D1 x
A, loop enlarges to measure penile girth in millimeters. B,
1 l' |6 u; ?3 J: [example of penile girth computed easily and accurately.
: P+ ~4 v4 `! B6 }! s" econversion of testosterone to dihydrotestosterone. It is in this7 K% u7 ~- F& @2 _7 Y& w
older group that others have noted high levels of serum
" }! r3 y$ X! z( {' ptestosterone with topical application. It would also appear
9 r' `9 Z* r& y' a, O# Xthat phallic response during puberty is related directly to the
' H) c$ p& B: w& |1 E- R( B( Userum testosterone level. There also is other evidence of local) S3 Q& T4 D1 g: c1 y
response to testosterone with hair growth and with spermato-( ]  `, \( Q9 O5 p$ N
genesis. 5• 61 B* j& u0 t( q& l7 I& F) {" P
Administration of larger doses of gonadotropin or systemic! N& f* M+ v; H
testosterone, as well as topical applications that produce
/ P7 ]* u  v1 O5 W9 W: |higher levels of serum testosterone (150 to 900 ng./dl.), will0 k' h/ C3 t  X, L; n2 d# O% X! ~
also produce phallic growth but risks accelerated skeletal
: O% T" v: t" l$ v6 gmaturation even after stopping treatment. It would appear9 n. A! `8 }% Q( `
that this may be avoided by topical applications of testosterone
) V% n( s. p( Tand monitoring of serum testosterone. Even with this control; D3 e7 \, c+ E0 J( H
the duration of our therapy did not exceed 3 weeks at any
$ s& e/ b/ k0 t2 \# ?0 itime. It is apparent that the prepuberal male subject may3 Z- j  m+ ~8 s5 P. X* h: Q/ H) A8 ]
suffer accelerated bone growth with testosterone levels near
5 j  M+ v6 |8 {* [5 @6 V0 ~# D( D200 ng./dl. When skeletal maturation is complete the level of
* r/ C8 A8 z$ C; k' \serum testosterone can be maintained in the 700 to 1,300 ng./! Q4 D9 D1 C% J
dl. range to stimulate phallic growth and secondary sexual
- I% ~$ o, m2 ?$ {4 q4 gchanges. Therefore, after skeletal maturation parenteral tes-
6 G5 O* k6 c6 u& O5 Btosterone may be used to advantage. Before skeletal matura-9 `# R: m- @4 G. N7 i
tion care must be taken to avoid maintaining levels of serum
; ^; r$ q2 s6 W/ k9 r1 Htestosterone more than 100 ng./dl. Low-dose gonadotropin
0 ?! f" u  |6 _9 u9 E- K) m8 d& Q1 Edepends upon intrinsic testicular activity and may require
" X) r- C; ^2 ~prolonged administration for any response.9 P0 G; C. g9 R3 H
Alternately, topical testosterone does not depend upon tes-2 J9 \/ {( ^) Z) u# P" J" W: \
ticular function and may provide a more constant level of
$ l4 N; y- F. ~- H0 SREFERENCES
. D  c4 E) v: B1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 U- [0 a% Y# N3 d) QR.: The local application of testosterone cream to the prepub-: |; h8 V9 G) }+ G2 }
ertal phallus. J. Urol., 105: 905, 1971.) ?& e+ ~4 U; }: B6 ]& E( f
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone/ }: m* z1 k; j" T
treatment for micropenis during early childhood. J. Pediat.,; P  a# ^; i, \# C
83: 247, 1973.
8 M3 Z7 A) M. s  d3 q* G) c3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& Z' Y$ W$ l7 u
one therapy for penile growth. Urology, 6: 708, 1975.
& {+ Y2 d" G! ~8 a) ^4 v4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 T1 G" l9 E' `# nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by2 d' l* z/ p' M$ j' @* p
skin slices of man. J. Clin. Invest., 48: 371, 1969.
8 j4 j  y6 H5 l$ r/ i5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
/ Z; h) |2 k6 ]3 X# m$ mby topical application of androgens. J.A.M.A., 191: 521, 1965.* ^  s8 q" n9 V! k# L7 g- H0 f% }
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 j1 v6 o$ j/ Z2 F1 }' ~androgenic effect of interstitial cell tumor of the testis. J.+ n0 m  @4 D- r0 y1 u/ `& q% a
Urol., 104: 774, 1970.: z0 N% S6 D8 A2 [" w
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
% `5 s- h8 O& W/ O5 Z. Btion in the male genitalia from birth to maturity. J. Urol., 48:
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