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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
) c/ k; a3 v) I2 |- l' gGONADOTROPIN
0 t. b- c+ r- U# {RICHARD C. KLUGO* AND JOSEPH C. CERNY
5 h  Q9 t5 y. M" c' t; H7 vFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 n- v) _3 z' WABSTRACT9 W; k: j+ Z# Q4 Q1 o% O( G+ J
Five patients were treated with gonadotropin and topical testosterone for micropenis associated! E$ W8 ^% v! j$ V4 k+ Z
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: o+ |% r& v& I8 Q; r! A# j
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
& F8 E( I0 U# K+ ?+ y0 Xcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 t& {5 J, F* y, L+ T; d5 H$ s6 lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 l1 l5 X; ?- v) Q5 ]8 c, z+ Z( G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 ]' N) B" D) D3 G: G6 |) Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 {' ^' W" j/ L; \2 J% ~/ C% c
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This! i8 C) W+ A4 a/ ?
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
+ P  F2 R9 S: n6 _+ ngrowth. The response appears to be greater in younger children, which is consistent with previ-
# l6 P% \, x2 X" q$ rously published studies of age-related 5 reductase activity.! t  S8 }# K  _; u3 w
Children with microphallus regardless of its etiology will
9 i8 t3 Y9 m: k$ ?2 yrequire augmentation or consideration for alteration of exter-
- |* H! ]! d/ D2 T8 `% fnal genitalia. In many instances urethroplasty for hypo-
% X$ T* w5 e/ }: o7 T; d) j. Dspadias is easier with previous stimulation of phallic growth.
& [) X9 ]5 V/ ]) ~' W; jThe use of testosterone administered parenterally or topically% y7 m9 b$ k. s2 G' [
has produced effective phallic growth. 1- 3 The mechanism of
  s* c: b/ l, [/ N' K! hresponse has been considered as local or systemic. With this
( i6 V. G7 {" ^8 Q6 Y; Q4 Jin mind we studied 5 children with microphallus for response3 t0 T* u4 B9 w. w; P( ~, w; P4 A# w& S
to gonadotropin and to topical testosterone independently.' u8 Q4 _+ m2 l1 p$ U8 m- F
MATERIALS AND METHODS
* a7 ~, N0 c5 y+ aFive 46 XY male subjects between 3 and 17 years old were; w. O' |# [1 X+ d% p; i' X6 c" u
evaluated for serum testosterone levels and hypothalamic
3 @8 b# n# Q# _1 F7 K0 xfunction. Of these 5 boys 2 were considered to have Kallmann's9 l3 N7 Q; ]2 ?' ~  _5 v- m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 G" y9 N7 q2 n! G7 q: Blamic deficiency. After evaluation of response to luteinizing
' J3 w- P: w4 g( o) j1 Xhormone-releasing hormone these patients were treated with
' W  m% V2 c8 s7 e1,000 units of gonadotropin weekly for 3 weeks. Six weeks
3 Z& K4 V. e; p# K/ ~6 r# C" D5 \after completion of gonadotropin therapy 10 per cent topical5 W* e$ G$ Y# N# E2 n' x9 ?
testosterone was applied to the phallus twice daily for 3 weeks.
0 |2 i  x7 r8 Y8 {7 G; `7 a7 c5 r, cSerum testosterone, luteinizing hormone and follicle-stimulat-
) n. M) E+ l7 j) g( hing hormone were monitored before, during and after comple-; o; L# Z8 X. {/ i9 k6 e0 `
tion of each phase of therapy. Penile stretch length was
# w" F6 G$ \+ ?2 Bobtained by measuring from the symphysis pubis to the tip of9 Y' {4 G  p: P) Y+ V( p7 E
the glans. Penile circumferential (girth) measurements were9 O2 |' ]$ j2 D. v0 V7 {' i
obtained using an orthopedic digital measuring device (see
3 s  {- z7 o0 n# o1 t  Jfigure).8 F, o, J$ t2 u4 I" \1 p
RESULTS) \/ i* o( q9 S' l: [
Serum testosterone increased moderately to levels between
- j  ]5 ?5 q* T* @* ]7 H. @# N0 G50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-. c: U3 ]5 n0 ]
terone levels with topical testosterone remained near pre-# ]' ~! g% T2 K/ F
treatment levels (35 ng./dl.) or were elevated to similar levels
4 Z2 ^9 z5 r7 a, \, Cdeveloped after gonadotropin therapy (96 ng./dl.). Higher
! u2 P' ^8 h7 z  k; @serum levels were noted in older patients (12 and 17 years old),
  V0 b; y% P3 o6 T6 _2 h# J" Zwhile lower levels persisted in younger patients (4, 8, and 10$ |/ M+ F. V9 i' z) L& z! U
years old) (see table). Despite absence of profound alterations) F& }; F/ x  H* d% n* S0 {
of serum testosterone the topical therapy provided a greater
  S7 r7 H) h# l+ HAccepted for publication July 1, 1977. ·+ t& b2 [7 K9 x2 @: O6 b
Read at annual meeting of American Urological Association,0 z9 `9 U1 F  V' K6 ]3 V8 R
Chicago, Illinois, April 24-28, 1977.
& X. }8 z: ?: P" ~( I4 q* Requests for reprints: Division of Urology, Henry Ford Hospital,$ \! A3 s# E7 |
2799 W. Grand Blvd., Detroit, Michigan 48202.
4 B/ r# r+ t: F3 pimprovement in phallic growth compared to gonadotropin.
* q- k9 g% a0 U! o5 R4 O  xAverage phallic growth with gonadotropin was 14.3 per cent
* c$ o/ ~* D7 O5 ~+ f4 T8 Sincrease in length and 5.0 per cent increase of girth. Topical
5 ?. P  H# ]3 g9 e' V( Qtestosterone produced a 60.0 per cent increase of phallic length. ^" A. Q! Z7 }  c0 P6 N5 d) o9 G
and 52.9 per cent increase of girth (circumference). The
. ?$ R) K& S6 Q& gresponse to topical testosterone was greatest in children be-2 T: ~' C" j+ P: i
tween 4 and 8 years old, with a gradual decrease to age 17
5 J0 J; \: X) V7 `years (see table).$ Z1 A9 p$ H( d8 \1 ?# b: g
DISCUSSION
2 }2 U. x; k& W8 ?9 H# JTopical testosterone has been used effectively by other
1 P' |* B: b/ Q8 r. uclinicians but its mode of action remains controversial. Im-3 ^0 k8 k) W- N% v7 t+ A7 n
mergut and associates reported an excellent growth response7 Q0 a5 [9 q  R
to topical testosterone with low levels of serum testosterone,
& h2 m6 a/ Z: H& |, Wsuggesting a local effect.1 Others have obtained growth re-2 u0 R+ ?, I5 k5 {5 ^: `
sponse with high. levels of serum testosterone after topical, i' D3 M( f. L2 ^0 P
administration, suggesting a systemic response. 3 The use of
$ P" h+ K. z* y4 \gonadotropin to obtain levels of serum testosterone compara-
+ O! O4 d: v: G: j8 Y* uble to levels obtained with topical testosterone would seem to
8 @: r  |; v' c7 Yprovide a means to compare the relative effectiveness of; r, O- X+ s# P; b- r# s5 {
topical testosterone to systemic testosterone effect. It cer-
1 F4 O- S, B% G* Rtainly has been established that gonadotropin as well as par-
$ C$ l+ A/ ]6 y( P3 Q2 a/ @6 c6 Penteral testosterone administration will produce genital' w  d6 M! ?! j9 F
growth. Our report shows that the growth of the phallus was
, a2 F9 {* L4 Xsignificantly greater with topical applications than with go-
- z7 P# y/ v. N/ S+ `! c, snadotropin, particularly in children less than 10 years old.; O$ ^* d# R4 Y# j+ }
The levels of serum testosterone remained similar or lower
& H2 s7 _' f9 U( i, e' Kthan with gonadotropin during therapy, suggesting that topi-- S, s3 i7 J3 E& |' Z1 K
cal application produces genital growth by its local effect as( X; c* c, X) n( T* q
well as its systemic effect.4 p3 W8 p2 w7 w% t+ u
Review of our patients and their growth response related to
& u" z, u) U5 @3 X8 Kage shows a greater growth response at an earlier age. This is
* t( ^) i) I7 b# vconsistent with the findings of Wilson and Walker, who
" C( a: B' V  z% Xreported an increased conversion of testosterone to dihydrotes-
9 M' w% B1 a$ U& F* h4 p, w: u# atosterone in the foreskin of neonates and infants.4 This activ-" [7 e3 p1 m! B% o. h7 F0 k, w
ity gradually decreases with age until puberty when it ap-
5 e0 P# V* O4 J; \0 M1 B, T% Aproaches the same level of activity as peripheral skin. It may
* x6 M5 Z; u4 Y6 {4 x' Hwell be that absorption of testosterone is less when applied at# I/ t4 M" D& _9 l9 g; K( K. f1 t1 f
an earlier age as suggested by lower serum levels in children) K4 g+ g0 o9 K
less than 10 years old. This fact may be explained by the- R/ [* a0 ^# d4 u6 o' k
greater ability of phallic skin to convert testosterone to dihy-8 I5 R5 E# s( X$ r, ~! R
drotestosterone at this age. Conversely, serum levels in older
  @0 n/ T4 K' D# v$ \patients were higher, possibly because of decreased local
) }+ r5 I9 |9 y! p0 g% T5 W* c667& x5 |' B9 u6 J+ t. s
668 KLUGO AND CERNY
7 `- ?, D% @1 ]. \6 z" h7 LPt. Age
$ B0 w! U5 P. j8 d4 w(yrs.)# i$ R2 a8 P1 x9 j4 L. y
Serum Testosterone Phallus (cm.) Change Length
$ D) p8 L# Z& m" a: j8 H! M; K(ng./dl.) Girth x Length (%)" W, m* N2 X! @5 f. m3 T
4# u- {% f" T* h# X; E
8- j& y  h: c! h. o7 v" U* |7 P, l0 \
10+ \4 ^' o8 Y" b+ P% q( k0 O5 x( D
12$ r5 m  j* a/ y* ^; C
17
7 o3 V( H$ `7 v4 G) {; Q* y* [Gonadotropin
, s. J6 D8 d/ X& L6 S71.6 2.0 X 3 16.6
1 l8 I5 o3 {3 ]  W, l$ R50.4 4.0 X 5.0 20.0
( A; A# r, z1 e- C+ o5 j5 U9 B22.0 4.5 X 4.0 25.0
. e" V0 Y. B- y2 N4 t3 z; z84.6 4.0 X 4.5 11.1
, L0 G1 {# `; P( O0 M& m85.9 4.5 X 5.5 9.0/ k9 }9 m, }3 U0 M9 ~0 T- D9 M0 V
Av. 14.3% L$ ~1 o  b4 o8 |. D# g/ [
4
# [& }( u9 ]3 B5 W8) a" K. K$ p1 n
10: x+ F" P0 h( S) g# b1 ?. `
12
; G. |+ W3 _- K- p, J9 Z17
2 ?. E2 }1 J% ]# b/ qTopical testosterone6 `% C. g) b) O- _' Q
34.6 4.5 X 6.5 85& i8 P1 f* M3 Z( R& S/ \( {
38.8 6.0 X 8.5 700 V- g* {4 P3 I3 S0 c4 \! T: l3 h' Z  m
40.0 6.0 X 6.5 62.5: O+ k# W& `& ]$ Y* h
93.6 6.0 X 7.0 55.5
& {5 j1 \8 z& V+ H. J, Y2 _* n95.0 6.5 X 7.0 27.2
* y* r% }, K, o+ z0 l3 I3 hAv. 60.0
. s7 @" Z5 p1 A: _7 K, I5 pavailable testosterone. Again, emphasis should be placed on
( M$ {- H0 p5 _: nearly therapy when lower levels of testosterone appear to; p6 ]% {0 y# m) z9 U7 X. R' {1 E
provide the best responses. The earlier therapy is instituted9 K$ q# h. _$ q/ L- x* `
the more likely there will be an excellent response with low
8 K! M) A: S, W6 k' {1 `3 C9 N" ~" rserum levels. Response occurs throughout adolescence as6 i/ I- u4 B3 V8 z% q3 d
noted in nomograms of phallic growth. 7 The actual response
9 I2 Q$ u) z3 k/ J" E* C9 m* ito a given serum level of testosterone is much greater at birth- C6 {8 p8 w% a5 k( Y4 C9 [
and gradually decreases as boys reach puberty. This is most$ s5 o+ d# s4 E( g$ h
likely related to the conversion of testosterone to dihydrotes-: ]2 r! ]6 ^! f5 X( j3 m5 d$ m4 s
tosterone and correlates well with the studies of testosterone
( J! j/ @5 J; c5 _- V9 yconversion in foreskin at various ages.4 z  Y/ a' Y" {* Y) A
The question arises regarding early treatment as to whether7 e9 q, Z0 p) ?3 f9 S/ G) [' ?
one might sacrifice ultimate potential growth as with acceler-
! U2 ^5 F+ U2 ]8 \2 _1 O$ Uated bone growth. The situation appears quite the reverse
6 K3 ?, S1 \6 N7 i3 d; dwith phallic response. If the early growth period is not used* G3 s" T# k" b
when 5a reductase activity is greatest then potential growth) g) X$ I1 B$ G/ ?
may be lost. We have not observed any regression of growth1 o5 g& X- y7 F) @% _
attained with topical or gonadotropin therapy. It may well
4 m$ N9 F/ \' t: }* N! @7 ]9 Obe that some patients will show little or no response to any, T( h9 o  P. B, Z& |# ?0 I1 p
form of therapy. This would suggest a defect in the ability to
$ r! J* F$ X- I9 x' Bconvert testosterone to dihydrotestosterone and indicate that
- _5 j4 C' c, a, _2 Cphallic and peripheral skin, and subcutaneous tissue should
& r7 B$ x. ?5 G6 L# Gbe compared for 5a reductase activity.0 O* @# m9 d3 g3 l6 g6 H! d8 K* M
A, loop enlarges to measure penile girth in millimeters. B,) j* u9 T; o1 ?5 L4 `1 w" T
example of penile girth computed easily and accurately.
3 H  f% Q: a- ~# n' _conversion of testosterone to dihydrotestosterone. It is in this" l+ D/ k, A0 Z. x# G* l1 v+ c
older group that others have noted high levels of serum
% S" y6 ]& |6 etestosterone with topical application. It would also appear$ x! F1 ~: x9 x  C3 H
that phallic response during puberty is related directly to the# m4 w2 d  e) w/ ^7 t# B+ |% {
serum testosterone level. There also is other evidence of local
; q) ^# u2 d, A& y8 K. ~% b- Q: @9 Xresponse to testosterone with hair growth and with spermato-
- J! n' I6 ~# U# \4 q. X  rgenesis. 5• 6
- A  u9 }) t) n: {Administration of larger doses of gonadotropin or systemic7 f' @- a/ o* `& c6 A  _
testosterone, as well as topical applications that produce5 ^6 l4 K. {) j5 i9 w6 C
higher levels of serum testosterone (150 to 900 ng./dl.), will+ H, D/ B* @) g( x6 }9 r  y% }4 e7 o
also produce phallic growth but risks accelerated skeletal" H1 p& F% L* x! V; d
maturation even after stopping treatment. It would appear
! @8 D1 I: z5 y# S5 e* k. G% N8 [that this may be avoided by topical applications of testosterone
# g; ?; e" ^+ P7 `% I" l, eand monitoring of serum testosterone. Even with this control! _# @! M- M3 H1 N' Y! ~" N
the duration of our therapy did not exceed 3 weeks at any
8 Q# _9 x7 h, w% H3 stime. It is apparent that the prepuberal male subject may
& X* O8 \+ i' ]1 y2 R* l( fsuffer accelerated bone growth with testosterone levels near" t0 _0 G6 W  e; t; [
200 ng./dl. When skeletal maturation is complete the level of, p- s. w; \7 {  U
serum testosterone can be maintained in the 700 to 1,300 ng./- p. c& D# ?/ q
dl. range to stimulate phallic growth and secondary sexual, g7 j; H2 j4 J; m" F% j( t
changes. Therefore, after skeletal maturation parenteral tes-
9 j* R- f2 I3 g2 x) `) \9 ytosterone may be used to advantage. Before skeletal matura-5 O8 r) G' q: T  G( T+ G
tion care must be taken to avoid maintaining levels of serum# {& M% c9 ?4 M1 @# W
testosterone more than 100 ng./dl. Low-dose gonadotropin5 R7 c6 j) T. I" U, K
depends upon intrinsic testicular activity and may require
" O7 @7 R4 [, n& o# M5 }- E9 Rprolonged administration for any response.
7 G/ _4 A4 @1 Q4 t! f9 H+ R, l7 m* gAlternately, topical testosterone does not depend upon tes-
9 G: D9 n. f! I- j  }' `4 J  Mticular function and may provide a more constant level of
8 ]9 r/ Z" K" L6 G- }9 rREFERENCES, m2 h$ a" R% `" m
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 R) g  N) d3 W3 _8 N( w6 L/ r
R.: The local application of testosterone cream to the prepub-
+ p. ?7 }0 k3 M+ G3 \# d7 nertal phallus. J. Urol., 105: 905, 1971.  z4 \' C. d- R, L  h( c2 `( c
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ n  m2 V" u! J; ntreatment for micropenis during early childhood. J. Pediat.,
: t. o" v+ M  y2 Q83: 247, 1973.
8 R7 `0 o! f" u5 J) D  Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-8 S; q/ j. w6 ^* O
one therapy for penile growth. Urology, 6: 708, 1975.. h- ^7 K7 F* t/ K/ m
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* O1 O: r2 E5 m7 i
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# H1 N  k' K" _/ r6 [& j
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 M/ \: H/ P4 z! e; J' H& p5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& ]6 i6 W* [  s1 E- f! nby topical application of androgens. J.A.M.A., 191: 521, 1965.
2 K5 z5 K! B  u% R, r6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local3 [4 ]% ^- Q$ l  b# I( o' ~6 v
androgenic effect of interstitial cell tumor of the testis. J.6 M, \' w# i4 E: ~0 b# v; U. a
Urol., 104: 774, 1970.0 `7 U# W  m- Q% Q
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ f6 V2 e: z# }3 A
tion in the male genitalia from birth to maturity. J. Urol., 48:
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