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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 l# Y1 ~7 o% J, j6 n
GONADOTROPIN* f4 b' [) ^# l9 f" L& ?9 \- N* W: M
RICHARD C. KLUGO* AND JOSEPH C. CERNY
" V6 K# T* X( H$ `" L: J- f; ~8 UFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' l, ~1 M1 P. a' V' M7 i. C1 wABSTRACT
) z. l, ?# b: P1 Z3 [! zFive patients were treated with gonadotropin and topical testosterone for micropenis associated, ?1 {3 p, T* |8 i/ Q0 k3 r
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ d+ ?9 c( d/ \0 F
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 P1 V# P  W$ P. u- Tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' Q3 Q$ i  X( U4 B! U" x% Q0 Y" O4 ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 c& P. l& \5 `' N* Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average( @; f( \2 i2 x0 T0 b0 E8 X; a. @' T0 U
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response1 ?# |+ {/ X$ S4 l! |. ]! }
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This' U* c2 F% @0 X; m+ I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! f, U( |, ~, ~) F
growth. The response appears to be greater in younger children, which is consistent with previ-& u% P. l- m% T$ i' [
ously published studies of age-related 5 reductase activity." m* F5 n, ^8 ], x& Z) d
Children with microphallus regardless of its etiology will8 j) I# Q) \, t) Z
require augmentation or consideration for alteration of exter-
, z( y0 c8 y" l; Q$ c5 @1 znal genitalia. In many instances urethroplasty for hypo-! o" c& \6 X2 x0 X; l/ K
spadias is easier with previous stimulation of phallic growth.& a4 L- A4 q: \9 s3 k- S1 r
The use of testosterone administered parenterally or topically
" f5 o5 H* V% c1 M/ s2 ohas produced effective phallic growth. 1- 3 The mechanism of% ]8 V- q7 ^+ T* q
response has been considered as local or systemic. With this
9 j/ F" D% q/ k' F4 y0 R4 Nin mind we studied 5 children with microphallus for response
# @3 L: z* ?% D% eto gonadotropin and to topical testosterone independently.
4 i9 F0 i/ [1 e6 u  o0 _MATERIALS AND METHODS8 f* J4 H8 t3 r+ u' H* L  Z
Five 46 XY male subjects between 3 and 17 years old were: |! _. U  y5 G; M% [; x3 v
evaluated for serum testosterone levels and hypothalamic/ \! c- w0 T/ G, o$ B% a
function. Of these 5 boys 2 were considered to have Kallmann's
3 k7 x; q8 X1 u7 ^, ?4 ?# `* ~syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 P7 Z6 \0 J. `6 \0 N( Hlamic deficiency. After evaluation of response to luteinizing) l$ \& V% q' Z  }" I+ T* k' W
hormone-releasing hormone these patients were treated with
4 ^* w5 v1 ]7 u9 X1,000 units of gonadotropin weekly for 3 weeks. Six weeks
- r; L! p3 l% f) M8 R, Uafter completion of gonadotropin therapy 10 per cent topical; ]5 j  j) }- C  H9 q  Z) r3 l7 a
testosterone was applied to the phallus twice daily for 3 weeks.
6 O  T  y# F& F/ o* BSerum testosterone, luteinizing hormone and follicle-stimulat-2 P$ o. I' B0 U, L( I  I0 d; o
ing hormone were monitored before, during and after comple-. S. n4 O7 X9 s
tion of each phase of therapy. Penile stretch length was5 ^5 M0 w" F* C8 K2 A3 [0 n" h
obtained by measuring from the symphysis pubis to the tip of
9 g; d! m! @- `. O: A+ l) P4 C0 kthe glans. Penile circumferential (girth) measurements were
) p; [* O' T# e. e( U, ^obtained using an orthopedic digital measuring device (see
' ~. B9 E- a: g+ Gfigure).0 X8 B% r. U, _$ a, D, Q
RESULTS! D2 v+ e9 ^, ^* [9 ~. v
Serum testosterone increased moderately to levels between, r/ W$ A: t2 C& m  q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 J8 t: e, J$ @( |9 o8 yterone levels with topical testosterone remained near pre-
8 T. A9 j9 N- m0 P  I/ o" Ptreatment levels (35 ng./dl.) or were elevated to similar levels0 m0 z4 g0 s& W5 r  a! I
developed after gonadotropin therapy (96 ng./dl.). Higher
/ l- |* n* r+ p6 s2 k7 `serum levels were noted in older patients (12 and 17 years old),
/ W+ z% [  v- X* ?while lower levels persisted in younger patients (4, 8, and 10& y# V2 @" A+ h7 B( M
years old) (see table). Despite absence of profound alterations+ f0 S5 ^0 q) Y7 D
of serum testosterone the topical therapy provided a greater7 q9 x& D1 b3 R" @  R7 }
Accepted for publication July 1, 1977. ·
$ H% u) E; x% c* {. q& f) NRead at annual meeting of American Urological Association,
) F2 m) s# m! b9 ?' ~Chicago, Illinois, April 24-28, 1977.: q! T' Y* J8 f* Z  C  G, r) o
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 q- m6 s# n0 n2799 W. Grand Blvd., Detroit, Michigan 48202., M) m( v) u% l+ s
improvement in phallic growth compared to gonadotropin.2 \5 \  `, e0 \# ~, V
Average phallic growth with gonadotropin was 14.3 per cent
' a* z! Q* i. u7 Z1 ^9 D+ xincrease in length and 5.0 per cent increase of girth. Topical7 N5 W5 K# ^2 o7 g# V" x3 B+ m
testosterone produced a 60.0 per cent increase of phallic length! V1 Z$ H* A% E* O" [1 Q
and 52.9 per cent increase of girth (circumference). The- h+ _5 Y" ?/ u
response to topical testosterone was greatest in children be-) q5 \1 g. D% f! `- e
tween 4 and 8 years old, with a gradual decrease to age 17
& w: j/ \' g. g" y' h% @  x" c3 I8 Qyears (see table).: h: p% a( U2 @2 Z
DISCUSSION' ?4 F2 m+ V* R' s7 U
Topical testosterone has been used effectively by other" X* L7 @5 o. q
clinicians but its mode of action remains controversial. Im-
3 z/ R& t8 R6 p7 V1 Q" B. jmergut and associates reported an excellent growth response
6 z) M& H* X4 K. Z. V" E5 {; @to topical testosterone with low levels of serum testosterone,
0 I6 i6 x: _9 J# E& bsuggesting a local effect.1 Others have obtained growth re-- h6 V: x; X3 Y( \4 w
sponse with high. levels of serum testosterone after topical/ F  ?! \# y0 ^7 V, z+ ?- \$ \
administration, suggesting a systemic response. 3 The use of$ g8 A2 I: D4 r$ ^; I
gonadotropin to obtain levels of serum testosterone compara-  \- s  ^2 M# U
ble to levels obtained with topical testosterone would seem to
' [. M8 E) q* `, v  Rprovide a means to compare the relative effectiveness of* P2 K9 H! S9 T
topical testosterone to systemic testosterone effect. It cer-
  X3 i. B1 m! h& Jtainly has been established that gonadotropin as well as par-
) F$ r: s: P; ^: r0 henteral testosterone administration will produce genital
& \+ i) M8 z, c, T; cgrowth. Our report shows that the growth of the phallus was
; U# [4 r. e$ V& Y3 ysignificantly greater with topical applications than with go-
; F% p- k) U2 R  [% x7 Ynadotropin, particularly in children less than 10 years old.3 s) q8 p0 C. S0 r2 j3 j) k
The levels of serum testosterone remained similar or lower
: `  X+ C, U$ L) ethan with gonadotropin during therapy, suggesting that topi-/ O2 v% s+ k8 r2 i
cal application produces genital growth by its local effect as
2 D9 j4 q. e1 k. x# Swell as its systemic effect.
5 ?- ~( ]% v, p. k) w2 J. \( HReview of our patients and their growth response related to
3 r- J, C( b8 b' G1 u! aage shows a greater growth response at an earlier age. This is' R9 o) }! C6 C  z$ n: R
consistent with the findings of Wilson and Walker, who) E4 g5 p. B9 |1 p/ Y
reported an increased conversion of testosterone to dihydrotes-
7 W/ M1 ~2 w- m7 e) Ztosterone in the foreskin of neonates and infants.4 This activ-' K0 N8 f5 R( [6 {# k
ity gradually decreases with age until puberty when it ap-
; F; Y3 X+ c+ |% e. w1 S: ]proaches the same level of activity as peripheral skin. It may( z. I6 K& F1 ]
well be that absorption of testosterone is less when applied at
4 ]9 B6 y6 e. l$ w2 t5 ran earlier age as suggested by lower serum levels in children$ P( R1 R6 G+ v, H9 ?1 q
less than 10 years old. This fact may be explained by the
" }. p$ R( u' A6 [; Vgreater ability of phallic skin to convert testosterone to dihy-2 v! i! _$ i3 R/ V) N6 N* h
drotestosterone at this age. Conversely, serum levels in older! ^. c" {4 S' Q; F: i
patients were higher, possibly because of decreased local5 _1 W# F0 d# z: \8 j, m4 {' X
667
. Q1 @+ G  Q/ y5 `668 KLUGO AND CERNY3 s4 W- X) V3 c9 ~
Pt. Age
' {8 {; G, A4 u" L8 w(yrs.)$ {) }3 m( J- F! C. C1 T9 A
Serum Testosterone Phallus (cm.) Change Length3 f) j0 t! G) v
(ng./dl.) Girth x Length (%)! C( \) t0 U4 a
4  F% H5 _6 K4 I$ Q# ^. F" |
8
4 Y7 ]" @7 b: _  `; T" U10
) Q+ u* l" M( D( v12
, ~2 C$ X9 W4 |3 Z0 ~3 n# J# H17/ n: t8 Z4 `) {9 q
Gonadotropin* {3 ^3 ~* w' Z: b, \5 `$ b0 {
71.6 2.0 X 3 16.6! M2 T5 o9 n: X
50.4 4.0 X 5.0 20.0
  G0 B- g' y! j9 |# s22.0 4.5 X 4.0 25.0) a8 L, e; s0 Q
84.6 4.0 X 4.5 11.1
3 Y9 F. l6 N9 ^0 l- Z% |* w5 {85.9 4.5 X 5.5 9.0
3 W/ c! U/ C9 m% nAv. 14.3, F" c5 o3 L  n5 P  a, H
4
$ z. M3 g2 X% m89 m* M9 Q& o+ m, M; e8 O1 ^0 F
10
; u$ w4 P  {8 O12
( \: F9 q4 N& A& d' s17* N7 U# |; p8 x* j) r
Topical testosterone
. R; L  C- [! e; H/ R34.6 4.5 X 6.5 85% b# ?$ W' W4 M; O" \+ c" G
38.8 6.0 X 8.5 700 v( U! y) d1 X+ Q6 O4 C4 S! ]
40.0 6.0 X 6.5 62.5
3 h# Z/ C# h6 L: H93.6 6.0 X 7.0 55.5/ P4 s4 {+ X7 j" i( c" T1 I' c
95.0 6.5 X 7.0 27.2
/ X5 G' H- T  C& |8 c% T: M+ l  SAv. 60.09 h7 A' G% A, k  c& g% P- W
available testosterone. Again, emphasis should be placed on- `8 M, B$ Z1 s( i
early therapy when lower levels of testosterone appear to
% ^# W9 t; i1 V' @3 n- K; o1 ~provide the best responses. The earlier therapy is instituted
" B/ N8 O) A  l2 h, R/ U( bthe more likely there will be an excellent response with low
8 A7 m9 U6 Z" ~! M0 `serum levels. Response occurs throughout adolescence as& T, A) {& ?  J4 J  d7 |! k: l+ \! m
noted in nomograms of phallic growth. 7 The actual response
& y* Z' |  x; W" y' F# y  Dto a given serum level of testosterone is much greater at birth
! ]( [, r1 ^. O  M. }  Hand gradually decreases as boys reach puberty. This is most& w; T0 f9 P: `. t: D( G1 n
likely related to the conversion of testosterone to dihydrotes-6 z9 o" u% a9 N
tosterone and correlates well with the studies of testosterone
0 \/ ^' q9 T0 s. `3 H4 S$ U( K- econversion in foreskin at various ages.& Y+ _7 W& k7 J" F! D
The question arises regarding early treatment as to whether
3 T6 Y# C( \* Yone might sacrifice ultimate potential growth as with acceler-, q: ?  B( m' a8 t
ated bone growth. The situation appears quite the reverse: Z+ T3 c! T5 p0 J  c8 ~4 S
with phallic response. If the early growth period is not used
& X: }! V5 n; |7 |# M3 Owhen 5a reductase activity is greatest then potential growth5 W" Z, j9 k, c
may be lost. We have not observed any regression of growth
3 z- Q1 ?1 e8 A. g& {attained with topical or gonadotropin therapy. It may well( p5 |8 s0 ~3 d+ l
be that some patients will show little or no response to any
) H$ D2 W3 B' M9 \form of therapy. This would suggest a defect in the ability to3 a* f/ k  ^6 U+ J7 Z# ^7 F" i
convert testosterone to dihydrotestosterone and indicate that
. B  A4 J/ U1 P3 n! H' |5 `: Jphallic and peripheral skin, and subcutaneous tissue should7 h, E/ }- {' |6 `" D) N
be compared for 5a reductase activity.
/ q$ v9 X! w, v% MA, loop enlarges to measure penile girth in millimeters. B,8 m, m. R7 ^/ y  r
example of penile girth computed easily and accurately.
7 f: _1 Z0 W* xconversion of testosterone to dihydrotestosterone. It is in this# {: e- j3 ~* G: i4 ^
older group that others have noted high levels of serum- V4 N% N% O$ t( Z
testosterone with topical application. It would also appear
/ C4 ~$ E  u" _. O' ?that phallic response during puberty is related directly to the" A$ Q7 B1 i: H* c: Z
serum testosterone level. There also is other evidence of local
! b( v5 a4 U/ ^9 w! j' cresponse to testosterone with hair growth and with spermato-1 K+ {% r+ A2 c7 R: r8 w% ?
genesis. 5• 6; i0 ^' o) K5 |6 h! j
Administration of larger doses of gonadotropin or systemic6 a/ H3 G7 |4 k/ l
testosterone, as well as topical applications that produce0 d3 `  B+ V, |% `, p" S
higher levels of serum testosterone (150 to 900 ng./dl.), will5 U% V  L4 p- V& D3 }. @; k
also produce phallic growth but risks accelerated skeletal5 F4 g9 e. m$ T* t2 e
maturation even after stopping treatment. It would appear& s* }+ O3 E) H4 p$ k
that this may be avoided by topical applications of testosterone& B( |! f1 ~: d; G
and monitoring of serum testosterone. Even with this control
% m# g) ~. b  L) v" X' }2 Athe duration of our therapy did not exceed 3 weeks at any
) G1 J# B/ g; l, ?5 Dtime. It is apparent that the prepuberal male subject may2 A' O* @9 N1 |& d
suffer accelerated bone growth with testosterone levels near6 H% Q& K9 D5 F9 V& M: O
200 ng./dl. When skeletal maturation is complete the level of. P5 |' a" q+ R0 z* B
serum testosterone can be maintained in the 700 to 1,300 ng./3 c! b" S6 ?* ]( v
dl. range to stimulate phallic growth and secondary sexual
* f8 C' v0 `$ t. d! A; C/ [changes. Therefore, after skeletal maturation parenteral tes-7 \3 u  A3 D9 p: d, G% w
tosterone may be used to advantage. Before skeletal matura-) ?4 A0 h( P8 |2 h1 z4 w$ p
tion care must be taken to avoid maintaining levels of serum: m4 M1 X/ z: v3 ~
testosterone more than 100 ng./dl. Low-dose gonadotropin
& U# N4 `+ d1 g3 ~depends upon intrinsic testicular activity and may require
/ I; d7 E9 W* h( `- f9 a6 ^5 C9 E$ eprolonged administration for any response.: @! A% e8 A* |! I: C. n: M$ `
Alternately, topical testosterone does not depend upon tes-
% V2 \1 d6 {! }& K/ Uticular function and may provide a more constant level of) K+ }" X/ g* ?' B" g
REFERENCES
( Y( E- v# K3 V0 s  b* o) \! ~1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
% F1 F; P- Z1 j  l/ }1 kR.: The local application of testosterone cream to the prepub-
& f% O5 ~4 J# {7 Y; U% }7 ]) zertal phallus. J. Urol., 105: 905, 1971.
0 y( d2 p# Z9 a' c( c2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 f. ?, U1 R2 H* }6 v6 c
treatment for micropenis during early childhood. J. Pediat.,. G! M: l+ P, f) I/ W: |7 Q
83: 247, 1973.0 f; Z/ P: a( X) }' ]4 ~( M
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-: O" ~$ j' }. t5 W( B, K( O  D
one therapy for penile growth. Urology, 6: 708, 1975.
1 n9 f. U8 D6 _* T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 [# k$ b- ^4 I" u* X; s3 [. u) n
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 w6 f! l% r0 D8 C( C
skin slices of man. J. Clin. Invest., 48: 371, 1969.  S& S7 y* I: O) S
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 \4 C! G8 @3 ?4 K7 |/ J; o0 B4 ]by topical application of androgens. J.A.M.A., 191: 521, 1965.
, ], P, ?; L2 ?7 }5 `7 K9 T6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; u  _+ s9 G& y' F
androgenic effect of interstitial cell tumor of the testis. J.' r* k' F( x8 L) V+ J8 F6 J' i
Urol., 104: 774, 1970.+ X1 ^2 \- U4 w! n8 h% ?' ^( R3 j
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
: f  n6 h- y# C; v- B; z/ Gtion in the male genitalia from birth to maturity. J. Urol., 48:
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